Rna encoding a therapeutic protein

ABSTRACT

The present invention relates to an RNA encoding a therapeutic protein. In particular, the present invention relates to RNA suitable for use as a medicament. The present invention concerns such novel RNA as well as compositions and kits comprising the RNA. Furthermore, the present invention relates to the RNA, compositions or kits as disclosed herein for use as a medicament. The present invention also provides the use of the RNA, compositions or kits as disclosed herein for increasing the expression of said encoded protein, in particular in gene therapy.

This application is a divisional of U.S. application Ser. No.16/098,844, filed Nov. 2, 2018, which is a national phase applicationunder 35 U.S.C. § 371 of International Application No.PCT/EP2017/060692, filed May 4, 2017, which claims benefit ofInternational Application No. PCT/EP2016/060111, filed May 4, 2016, theentire contents of each of which are hereby incorporated by reference.

The sequence listing that is contained in the file named“CRVCP0222USD1_ST25.txt”, which is 224 MB (as measured in MicrosoftWindows®) and was created on Jun. 26, 2021, is filed concurrentlyherewith on compact discs by Priority Express Mail and is IDincorporated by reference herein.

The present invention relates to an RNA encoding a therapeutic protein.In particular, the present invention relates to RNA suitable for use asa medicament. The present invention concerns such novel RNA as well ascompositions and kits comprising the RNA. Furthermore, the presentinvention relates to the RNA, compositions or kits as disclosed hereinfor use as a medicament. The present invention also provides the use ofthe RNA, compositions or kits as disclosed herein for increasing theexpression of said encoded protein, in particular in gene therapy.

In gene therapy, nucleic acids are typically used as a pharmaceuticalagent for treating a disease. It derives its name from the idea thatnucleic acids can be used to supplement or alter the expression of agene within an individual's cells as a therapy for treating orpreventing a disease. The most common form of gene therapy involves theuse of nucleic acids encoding a functional, therapeutic protein in orderto replace a mutated gene. Other approaches involve direct correction ofa mutation, or using nucleic acids that encode a therapeutic proteindrug to provide treatment.

Gene therapy is a method of molecular medicine, which have already beenproven in the therapy and prevention of certain diseases and generallyexhibit a considerable effect on daily medical practice, in particularon the treatment or prevention of diseases as mentioned herein. Genetherapy is based on the introduction of a nucleic acid into a patient'scells or tissue and subsequent processing of the information encoded bythe nucleic acid that has been introduced into the cells or tissue, thatis to say the (protein) expression of the desired polypeptides.

Gene therapy may be beneficial for a large number of inherited oracquired diseases, inter alis infectious diseases, neoplasms (e.g.cancer or tumour diseases), diseases of the blood and blood-formingorgans, endocrine, nutritional and metabolic diseases, diseases of thenervous system, diseases of the circulatory system, diseases of therespiratory system, diseases of the digestive system, diseases of theskin and subcutaneous tissue, diseases of the musculoskeletal system andconnective tissue, and diseases of the genitourinary system.

In gene therapy approaches, typically DNA is used even though RNA isalso known in recent developments. Importantly, in all these genetherapy approaches mRNA functions as messenger for the sequenceinformation of the encoded protein, irrespectively of whether DNA, viralRNA or mRNA is used.

In general RNA is considered an unstable molecule: RNases are ubiquitousand notoriously difficult to inactivate. Furthermore, RNA is alsochemically more labile than DNA. Also for that reason, many gene therapyapproaches normally use DNA to transfer the coding information into thecell, which is then transcribed into mRNA, carrying naturally occurringelements of an mRNA, such as a 5′-CAP structure and a 3′ poly(A)sequence to ensure expression of the encoded therapeutic protein.

However, in many cases expression systems based on the introduction ofsuch nucleic acids into the patient's cells or tissue and the subsequentexpression of the desired polypeptides encoded by these nucleic acids donot exhibit the desired, or even the required, level of expression whichmay allow for an efficient therapy, irrespectively of whether DNA or RNAis used.

In the prior art, different attempts have hitherto been made to increasethe yield of the expression of an encoded protein, in particular by useof improved expression systems, both in vitro and/or in viva. Methodsfor increasing expression described generally in the prior art areconventionally based on the use of expression vectors or cassettescontaining specific promoters and corresponding regulation elements. Asthese expression vectors or cassettes are typically limited toparticular cell systems, these expression systems have to be adapted foruse in different cell systems. Such adapted expression vectors orcassettes are then usually transfected into the cells, which aretypically treated depending on the specific cell line. Therefore,preference is given primarily to those nucleic acid molecules which arecapable of expressing the encoded proteins in a target cell by systemsinherent in the cell, independent of promoters and regulation elementswhich are specific for particular cell types. In this context, there canbe distinguished between mRNA stabilizing elements and elements, whichincrease translation efficiency of mRNA.

mRNAs which are optimized in their coding sequence and which aregenerally suitable for such a purpose are described in application WO02/098443 (CureVac GmbH). For example, WO 02/098443 describes mRNAs thatare stabilised in general form and optimised for translation in theircoding regions. WO 02/098443 further discloses a method for determiningsequence modifications. WO 02/098443 additionally describespossibilities for substituting adenine and uracil nucleotides in mRNAsequences in order to increase the guanine/cytosine (G/C) content of thesequences. According to WO 02/098443, such substitutions and adaptationsfor increasing the G/C content can be used for gene therapeuticapplications but also genetic vaccines in the treatment of cancer orinfectious diseases. In this context, WO 02/098443 generally mentionssequences as a base sequence for such modifications, in which themodified mRNA codes for at least one biologically active peptide orpolypeptide, which is translated in the patient to be treated, forexample, either not at all or inadequately or with faults.Alternatively, WO 02/098443 proposes mRNAs coding for antigens e.g.tumour antigens or viral antigens as a base sequence for suchmodifications.

In a further approach to increase the expression of an encoded proteinthe application WO 2007/036366 describes the positive effect of longpoly(A) sequences (particularly longer than 120 bp) and the combinationof at least two 3′ untranslated regions of the beta globin gene on mRNAstability and translational activity.

However, even though some of these prior art documents try to providequite efficient tools for gene therapy approaches and additionallyimproved mRNA stability and translational activity, there still remainsthe problem of a generally lower stability of RNA-based applicationsversus DNA vaccines and DNA based gene therapeutic approaches.Accordingly, there still exists a need in the art to provide improvedtools for gene therapy approaches or as a supplementary therapy forconventional treatments as discussed above, which allow for betterprovision of encoded proteins in viva, e.g. via further improved mRNAstability and/or translational activity, preferably for gene therapy.

Furthermore despite of all progress in the art, efficient expression ofan encoded peptide or protein in cell-free systems, cells or organisms(recombinant expression) is still a challenging problem.

It is thus an object of the present invention to provide a systemsuitable for use in gene therapy. In particular, it is an object toprovide a system for expressing a therapeutic protein, preferably bystabilization of the mRNA and/or an increase of the translationalefficiency of such an mRNA with respect to such nucleic acids known fromthe prior art. It is a further object of the invention to provide such asystem, which allows treatment and/or prophylaxis of inherited oracquired diseases, particulary as defined herein, in a safe andeffective manner.

The object underlying the present invention is solved by the claimedsubject matter.

The present application is filed together with a sequence listing inelectronic format. The sequence listing is provided as a file entitledCU01P222W02_SEQlist.txt, created on Apr. 28, 2017, which is 229,437 KBin size. The information contained in the electronic format of thesequence listing filed together with this application is incorporatedherein by reference in its entirety. Where reference is made herein to a“SEQ ID NO:”, the corresponding nucleic acid sequence or amino acidsequence in the sequence listing having the respective identifier isreferred to.

For the sake of clarity and readability the following definitions areprovided. Any technical feature mentioned for these definitions may beread on each and every embodiment of the invention. Additionaldefinitions and explanations may be specifically provided in the contextof these embodiments.

Adaptive immune response: The adaptive immune response is typicallyunderstood to be an antigen-specific response of the immune system.Antigen specificity allows for the generation of responses that aretailored, for example, to specific pathogens or pathogen-infected cells.The ability to mount these tailored responses is usually maintained inthe body by “memory cells”. Should a pathogen infect the body more thanonce, these specific memory cells are used to quickly eliminate it. Inthis context, the first step of an adaptive immune response is theactivation of naive antigen-specific T cells or different immune cellsable to induce an antigen-specific immune response by antigen-presentingcells. This occurs in the lymphoid tissues and organs through whichnaive T cells are constantly passing. The three cell types that mayserve as antigen-presenting cells are dendritic cells, macrophages, andB cells. Each of these cells has a distinct function in eliciting immuneresponses. Dendritic cells may take up antigens by phagocytosis andmacropinocytosis and may become stimulated by contact with e.g. aforeign antigen to migrate to the local lymphoid tissue, where theydifferentiate into mature dendritic cells. Macrophages ingestparticulate antigens such as bacteria and are induced by infectiousagents or other appropriate stimuli to express MHC molecules. The uniqueability of B cells to bind and internalize soluble protein antigens viatheir receptors may also be important to induce T cells. MHS-moleculesare, typically, responsible for presentation of an antigen to T-cells.Therein, presenting the antigen on MHS molecules leads to activation ofT cells, which induces their proliferation and differentiation intoarmed effector T cells. The most important function of effector T cellsis the killing of infected cells by CD8+ cytotoxic T cells and theactivation of macrophages by Th1 cells, which together make upcell-mediated immunity, and the activation of B cells by both Th2 andTh1 cells to produce different classes of antibody, thus driving thehumoral immune response. T cells recognize an antigen by their T cellreceptors which do not recognize and bind the antigen directly, butinstead recognize short peptide fragments e.g. of pathogen-derivedprotein antigens, e.g. so-called epitopes, which are bound to MHCmolecules on the surfaces of other cells.

Adaptive immune system: The adaptive immune system is essentiallydedicated to eliminate or prevent pathogenic growth. It typicallyregulates the adaptive immune response by providing the vertebrateimmune system with the ability to recognize and remember specificpathogens (to generate immunity), and to mount stronger attacks eachtime the pathogen is encountered. The system is highly adaptable becauseof somatic hypermutation (a process of accelerated somatic mutations),and V(D)J recombination (an irreversible genetic recombination ofantigen receptor gene segments). This mechanism allows a small number ofgenes to generate a vast number of different antigen receptors, whichare then uniquely expressed on each individual lymphocyte. Because thegene rearrangement leads to an irreversible change in the DNA of eachcell, all of the progeny (offspring) of such a cell will then inheritgenes encoding the same receptor specificity, including the Memory Bcells and Memory T cells that are the keys to long-lived specificimmunity.

Adjuvant/adjuvant component: An adjuvant or an adjuvant component in thebroadest sense is typically a pharmacological and/or immunological agentthat may modify, e.g. enhance, the effect of other agents, such as adrug or vaccine. It is to be interpreted in a broad sense and refers toa broad spectrum of substances. Typically, these substances are able toincrease the immunogenicity of antigens. For example, adjuvants may berecognized by the innate immune systems and, e.g., may elicit an innateimmune response. “Adjuvants” typically do not elicit an adaptive immuneresponse. Insofar, “adjuvants” do not qualify as antigens. Their mode ofaction is distinct from the effects triggered by antigens resulting inan adaptive immune response.

Antigen: In the context of the present invention, the term “antigen”typically refers to a substance, which is capable of being recognized bythe immune system, preferably by the adaptive immune system, and whichis capable of eliciting an antigen-specific immune response, e.g. byformation of antibodies and/or antigen-specific T cells as part of anadaptive immune response. Typically, an antigen may be or may comprise apeptide or protein, which may be presented by the MHC to T-cells. Inthis context, also fragments, variants and derivatives of an antigen,such as a peptide or a protein, comprising at least one epitope areunderstood as antigens.

Artificial nucleic acid molecule: An artificial nucleic acid moleculemay typically be understood to be a nucleic acid molecule, e.g. a DNA oran RNA that does not occur naturally. In other words, an artificialnucleic acid molecule may be understood as a non-natural nucleic acidmolecule. Such nucleic acid molecule may be non-natural due to itsindividual sequence (which does not occur naturally) and/or due to othermodifications, e.g. structural modifications of nucleotides, which donot occur naturally. An artificial nucleic acid molecule may be a DNAmolecule, an RNA molecule or a hybrid-molecule comprising DNA and RNAportions. Typically, artificial nucleic acid molecules may be designedand/or generated by genetic engineering methods to correspond to adesired artificial sequence of nucleotides (heterologous sequence). Inthis context, an artificial sequence is usually a sequence that may notoccur naturally, i.e. it differs from the wild type sequence by at leastone nucleotide. The term “wild type” may be understood as a sequenceoccurring in nature. Further, the term “artificial nucleic acidmolecule” is not restricted to mean “one single molecule” but is,typically, understood to comprise an ensemble of identical molecules.Accordingly, it may relate to a plurality of identical moleculescontained in an aliquot.

Bicistronic RNA, multicistronic RNA: A bicistronic or multicistronic RNAis typically an RNA, preferably an mRNA, that typically may have two(bicistronic) or more (multicistronic) open reading frames (DRF). Anopen reading frame in this context is a sequence of codons that istranslatable into a peptide or protein.

Carrier/polymeric carrier: A carrier in the context of the invention maytypically be a compound that facilitates transport and/or complexationof another compound (cargo). A polymeric carrier is typically a carrierthat is formed of a polymer. A carrier may be associated with its cargoby covalent or non-covalent interaction. A carrier may transport nucleicacids, e.g. RNA or DNA, to the target cells. The carrier may—for someembodiments—be a cationic component.

Cationic component: The term “cationic component” typically refers to acharged molecule, which is positively charged (cation) at a pH valuetypically from 1 to 9, preferably at a pH value of or below 9 (e.g. from5 to 9), of or below 8 (e.g. from 5 to 8), of or below 7 (e.g. from 5 to7), most preferably at a physiological pH, e.g. from 7.3 to 7.4.Accordingly, a cationic component may be any positively charged compoundor polymer, preferably a cationic peptide or protein, which ispositively charged under physiological conditions, particularly underphysiological conditions in viva. A “cationic peptide or protein” maycontain at least one positively charged amino acid, or more than onepositively charged amino acid, e.g. selected from Arg, His, Lys or kn.Accordingly, “polycationic” components are also within the scopeexhibiting more than one positive charge under the conditions given.

5′-cap: A 5′-cap is an entity, typically a modified nucleotide entity,which generally “caps” the 5′-end of a mature mRNA. A 5′-cap maytypically be formed by a modified nucleotide, particularly by aderivative of a guanine nucleotide. Preferably, the 5′-cap is linked tothe 5′-terminus via a 5′-5′-triphosphate linkage. A 5′-cap may bemethylated, e.g. m7GpppN, wherein N is the terminal 5′ nucleotide of thenucleic acid carrying the 5′-cap, typically the 5′-end of an RNA.Further examples of 5′ cap structures include glyceryl, inverted deoxyabasic residue (moiety), 4′,5′ methylene nucleotide,1-(beth-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide, carbocyclicnucleotide, 1,5-anhydrohexitol nucleotide, L-nucleotides,alpha-nucleotide, modified ID base nucleotide, threo-pentofuranosylnucleotide, acyclic 3′,4′-seco nucleotide, acyclic 3,4-dihydroxybutylnucleotide, acyclic 3,5 dihydroxypentyl nucleotide, 3′-3′-invertednucleotide moiety, 3′-3′-inverted abasic moiety, 3′-2′-invertednucleotide moiety, 3′-2′-inverted abasic moiety, 1,4-butanediolphosphate, 3′-phosphoramidate, hexylphosphate, aminohexyl phosphate,3′-phosphate, 3′ phosphorothioate, phosphorodithioate, or bridging ornon-bridging methylphosphonate moiety.

Cellular immunity/cellular immune response: Cellular immunity relatestypically to the activation of macrophages, natural killer cells (NK),antigen-specific cytotoxic T-lymphocytes, and the release of variouscytokines in response to an antigen. In more general terms, cellularimmunity is not based on antibodies, but on the activation of cells ofthe immune system. Typically, a cellular immune response may becharacterized e.g. by activating antigen-specific cytotoxicT-lymphocytes that are able to induce apoptosis in cells, e.g. specificimmune cells like dendritic cells or other cells, displaying epitopes offoreign antigens on their surface. Such cells may be virus-infected orinfected with intracellular bacteria, or cancer cells displaying tumorantigens. Further characteristics may be activation of macrophages andnatural killer cells, enabling them to destroy pathogens and stimulationof cells to secrete a variety of cytokines that influence the functionof other cells involved in adaptive immune responses and innate immuneresponses.

DNA: DNA is the usual abbreviation for deoxy-ribonucleic acid. It is anucleic acid molecule, i.e. a polymer consisting of nucleotides. Thesenucleotides are usually deoxy-adenosine-monophosphate,deoxy-thymidine-monophosphate, deoxy-guanosine-monophosphate anddeoxy-cytidine-monophosphate monomers which are—by themselves—composedof a sugar moiety (deoxyribose), a base moiety and a phosphate moiety,and polymerise by a characteristic backbone structure. The backbonestructure is, typically, formed by phosphodiester bonds between thesugar moiety of the nucleotide, i.e. deoxyribose, of a first and aphosphate moiety of a second, adjacent monomer. The specific order ofthe monomers, i.e. the order of the bases linked to thesugar/phosphate-backbone, is called the DNA sequence. DNA may be singlestranded or double stranded. In the double stranded form, thenucleotides of the first strand typically hybridize with the nucleotidesof the second strand, e.g. by A/T-base-pairing and G/C-base-pairing.

Epitope: In the context of the present invention, the term “epitope”typically refers to a fragment of an antigen or a variant of an antigen,wherein said fragment is presented by an MHC complex. Such a fragmentcomprising or consisting of an epitope as used herein may typicallycomprise from about 5 to about 20 amino acids. An epitope may also bereferred to herein as “antigen determinant”. Epitopes can bedistinguished in T cell epitopes and B cell epitopes. T cell epitopes orparts of the proteins in the context of the present invention maycomprise fragments preferably having a length of about 6 to about 20 oreven more amino acids, e.g. fragments as processed and presented by MHCclass I molecules, preferably having a length of about 8 to about 10amino acids, e.g. 8, 9, or 10, (or even 11, or 12 amino acids), orfragments as processed and presented by MHC class II molecules,preferably having a length of about 13 or more amino acids, e.g. 13, 14,15, 16, 17, 18, 19, 20 or even more amino acids, wherein these fragmentsmay be selected from any part of the amino acid sequence. Thesefragments are typically recognized by T cells in form of a complexconsisting of the peptide fragment and an MHC molecule, i.e. thefragments are typically not recognized in their native form. B cellepitopes are typically fragments located on the outer surface of(native) protein or peptide antigens as defined herein, preferablyhaving 5 to 15 amino acids, more preferably having 5 to 12 amino acids,even more preferably having 6 to 9 amino acids, which may be recognizedby antibodies, i.e. in their native form. Such epitopes of proteins orpeptides may furthermore be selected from any of the herein mentionedvariants of such proteins or peptides. In this context, antigenicdeterminants can be conformational or discontinuous epitopes, which arecomposed of segments of the proteins or peptides as defined herein thatare discontinuous in the amino acid sequence of the proteins or peptidesas defined herein but are brought together in the three-dimensionalstructure or continuous or linear epitopes, which are composed of asingle polypeptide chain.

Fragment of a sequence: A fragment of a sequence may typically be ashorter portion of a full-length sequence of e.g. a nucleic acidmolecule or an amino acid sequence. Accordingly, a fragment, typically,consists of a sequence that is identical to the corresponding stretchwithin the full-length sequence. A preferred fragment of a sequence inthe context of the present invention, consists of a continuous stretchof entities, such as nucleotides or amino acids corresponding to acontinuous stretch of entities in the molecule the fragment is derivedfrom, which represents at least 20%, preferably at least 30%, morepreferably at least 40%, more preferably at least 50%, even morepreferably at least 60%, even more preferably at least 70%, and mostpreferably at least 80% of the total (i.e. full-length) molecule, fromwhich the fragment is derived.

G/C modified: A G/C-modified nucleic acid may typically be a nucleicacid, preferably an artificial nucleic acid molecule as defined herein,based on a modified wild type sequence comprising a preferably increasednumber of guanosine and/or cytosine nucleotides as compared to the wildtype sequence. Such an increased number may be generated by substitutionof codons containing adenosine or thymidine nucleotides by codonscontaining guanosine or cytosine nucleotides. If the enriched G/Ccontent occurs in a coding region of DNA or RNA, it makes use of thedegeneracy of the genetic code. Accordingly, the codon substitutionspreferably do not alter the encoded amino acid residues, but exclusivelyincrease the G/C content of the nucleic acid molecule. As used herein,the term “G/C modification” comprises, in particular, the modificationsof the number of guanosine and/or cytosine nucleotides in the RNAaccording to the invention, such as GC optimization of sequences,adaptation of sequences to human codon usage, codon optimization, orC-optimization of sequences.

Gene therapy: Gene therapy may typically be understood to mean atreatment of a patient's body or isolated elements of a patient's body,for example isolated tissues/cells, by nucleic acids encoding a peptideor protein. It typically may comprise at least one of the steps of a)administration of a nucleic acid, preferably an RNA as defined herein,directly to the patient—by whatever administration route—or in vitro toisolated cells/tissues of the patient, which results in transfection ofthe patient's cells either in vivol ex vivo or in vitro; b)transcription and/or translation of the introduced nucleic acidmolecule; and optionally c) re-administration of isolated, transfectedcells to the patient, if the nucleic acid has not been administered IDdirectly to the patient. The term “gene therapy” as used hereintypically comprises treatment as well as prevention or prophylaxis of adisease.

Heterologous sequence: Two sequences are typically understood to be“heterologous” if they are not derivable from the same gene. I.e.,although heterologous sequences may be derivable from the same organism,they naturally (in nature) do not occur in the same nucleic acidmolecule, such as in the same mRNA.

Humoral immunity/humoral immune response: Humoral immunity referstypically to antibody production and optionally to accessory processesaccompanying antibody production. A humoral immune response may betypically characterized, e.g., by Th2 activation and cytokineproduction, germinal center formation and isotype switching, affinitymaturation and memory cell generation. Humoral immunity also typicallymay refer to the effector functions of antibodies, which includepathogen and toxin neutralization, classical complement activation, andopsonin promotion of phagocytosis and pathogen elimination.

Immunogen: In the context of the present invention, an immunogen may betypically understood to be a compound that is able to stimulate animmune response. Preferably, an immunogen is a peptide, polypeptide, orprotein. In a particularly preferred embodiment, an immunogen in thesense of the present invention is the product of translation of aprovided nucleic acid molecule, preferably an artificial nucleic acidmolecule as defined herein. Typically, an immunogen elicits at least anadaptive immune response.

Immunostimulatory composition: In the context of the invention, animmunostimulatory composition may be typically understood to be acomposition containing at least one component which is able to induce animmune response or from which a component, which is able to induce animmune response, is derivable. Such immune response may be preferably aninnate immune response or a combination of an adaptive and an innateimmune response. Preferably, an immunostimulatory composition in thecontext of the invention contains at least one artificial nucleic acidmolecule, more preferably an RNA, for example an mRNA molecule. Theimmunostimulatory component, such as the mRNA may be complexed with asuitable carrier. Thus, the immunostimulatory composition may comprisean mRNA/carrier-complex. Furthermore, the immunostimulatory compositionmay comprise an adjuvant and/or a suitable vehicle for theimmunostimulatory component, such as the mRNA.

Immune response: An immune response may typically be a specific reactionof the adaptive immune system to a particular antigen (so calledspecific or adaptive immune response) or an unspecific reaction of theinnate immune system (so called unspecific or innate immune response),or a combination thereof.

Immune system: The immune system may protect organisms from infection.If a pathogen succeeds in passing a physical barrier of an organism andenters this organism, the innate immune system provides an immediate,but non-specific response. If pathogens evade this innate response,vertebrates possess a second layer of protection, the adaptive immunesystem. Here, the immune system adapts its response during an infectionto improve its recognition of the pathogen. This improved response isthen retained after the pathogen has been eliminated, in the form of animmunological memory, and allows the adaptive immune system to mountfaster and stronger attacks each time this pathogen is encountered.According to this, the immune system comprises the innate and theadaptive immune system. Each of these two parts typically contains socalled humoral and cellular components.

Immunostimulatory RNA: An immunostimulatory RNA (isRNA) in the contextof the invention may typically be an RNA that is able to induce aninnate immune response. It usually does not have an open reading frameand thus does not provide a peptide-antigen or immunogen but elicits animmune response e.g. by binding to a specific kind of Toll-like-receptor(TLR) or other suitable receptors. However, of course also mRNAs havingan open reading frame and coding for a peptide/protein may induce aninnate immune response and, thus, may be immunostimulatory RNAs.

Innate immune system: The innate immune system, also known asnon-specific (or unspecific) immune system, typically comprises thecells and mechanisms that defend the host from infection by otherorganisms in a non-specific manner. This means that the cells of theinnate system may recognize and respond to pathogens in a generic way,but unlike the adaptive immune system, it does not confer long-lastingor protective immunity to the host. The innate immune system may be,e.g., activated by ligands of Toll-like receptors (TLRs) or otherauxiliary substances such as lipopolysaccharides, TNF-alpha, CD40ligand, or cytokines, monokines, lymphokines, interleukins orchemokines, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10,IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20,IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30,IL-31, IL-32, IL-33, IFN-alpha, IFN-beta, IFN-gamma, GM-CSF, G-CSF,M-CSF, LT-beth, TNF-alpha, growth factors, and hGH, a ligand of humanToll-like receptor TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9,TLR10, a ligand of murine Toll-like receptor TLR1, TLR2, TLR3, TLR4,TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 or TLR13, a ligand ofa NOD-like receptor, a ligand of a RIG-1 like receptor, animmunostimulatory nucleic acid, an immunostimulatory RNA (isRNA), aCpG-DNA, an antibacterial agent, or an anti-viral agent. Thepharmaceutical composition according to the present invention maycomprise one or more such substances. Typically, a response of theinnate immune system includes recruiting immune cells to sites ofinfection, through the production of chemical factors, includingspecialized chemical mediators, called cytokines; activation of thecomplement cascade; identification and removal of foreign substancespresent in organs, tissues, the blood and lymph, by specialized whiteblood cells; activation of the adaptive immune system; and/or acting asa physical and chemical barrier to infectious agents.

Cloning site: A cloning site is typically understood to be a segment ofa nucleic acid molecule, which is suitable for insertion of a nucleicacid sequence, e.g., a nucleic acid sequence comprising an open readingframe. Insertion may be performed by any molecular biological methodknown to the one skilled in the art, e.g. by restriction and ligation. Acloning site typically comprises one or more restriction enzymerecognition sites (restriction sites). These one or more restrictionssites may be recognized by restriction enzymes which cleave the DNA atthese sites. A cloning site which comprises more than one restrictionsite may also be termed a multiple cloning site (MCS) or a polylinker.

Nucleic acid molecule: A nucleic acid molecule is a molecule comprising,preferably consisting of nucleic acid components. The term nucleic acidmolecule preferably refers to DNA or RNA molecules. It is preferablyused synonymous with the term “polynucleotide”. Preferably, a nucleicacid molecule is a polymer comprising or consisting of nucleotidemonomers, which are covalently linked to each other byphosphodiester-bonds of a sugar/phosphate-backbone. The term “nucleicacid molecule” also encompasses modified nucleic acid molecules, such asbase-modified, sugar-modified or backbone-modified etc. DNA or RNAmolecules.

Open reading frame: An open reading frame (DRF) in the context of theinvention may typically be a sequence of several nucleotide triplets,which may be translated into a peptide or protein. An open reading framepreferably contains a start codon, i.e. a combination of threesubsequent nucleotides coding usually for the amino acid methionine(ATG), at its 5′-end and a subsequent region, which usually exhibits alength which is a multiple of 3 nucleotides. An ORF is preferablyterminated by a stop-codon (e.g., TAA, TAG, TGA). Typically, this is theonly stop-codon of the open reading frame. Thus, an open reading framein the context of the present invention is preferably a nucleotidesequence, consisting of a number of nucleotides that may be divided bythree, which starts with a start codon (e.g. ATG) and which preferablyterminates with a stop codon (e.g., TAA, TGA, or TAG). The open readingframe may be isolated or it may be incorporated in a longer nucleic acidsequence, for example in a vector or an mRNA. An open reading frame mayalso be termed “(protein) coding region” or, preferably, “codingsequence”.

Peptide: A peptide or polypeptide is typically a polymer of amino acidmonomers, linked by peptide bonds. It typically contains less than 50monomer units. Nevertheless, the term peptide is not a disclaimer formolecules having more than 50 monomer units. Long peptides are alsocalled polypeptides, typically having between 50 and 600 monomericunits.

Pharmaceutically effective amount: A pharmaceutically effective amountin the context of the invention is typically understood to be an amountthat is sufficient to induce a pharmaceutical effect, such as an immuneresponse, altering a pathological level of an expressed peptide orprotein, or substituting a lacking gene product, e.g., in case of apathological situation.

Protein: A protein typically comprises one or more peptides orpolypeptides. A protein is typically folded into 3-dimensional form,which may be required for the protein to exert its biological function.

Poly(A) sequence: A poly(A) sequence, also called poly(A) tail or3′-poly(A) tail, is typically understood to be a sequence of adenosinenucleotides, e.g., of up to about 400 adenosine nucleotides, e.g. fromabout 20 to about 400, preferably from about 50 to about 400, morepreferably from about 50 to about 300, even more preferably from about50 to about 250, most preferably from about 60 to about 250 adenosinenucleotides. As used herein, a poly(A) sequence may also comprise about10 to 200 adenosine nucleotides, preferably about 10 to 100 adenosinenucleotides, more preferably about 40 to 80 adenosine nucleotides oreven more preferably about 50 to 70 adenosine nucleotides. A poly(A)sequence is typically located at the 3′-end of an mRNA. In the contextof the present invention, a poly(A) sequence may be located within anmRNA or any other nucleic acid molecule, such as, e.g., in a vector, forexample, in a vector serving as template for the generation of an RNA,preferably an mRNA, e.g., by transcription of the vector.

Polyadenylation: Polyadenylation is typically understood to be theaddition of a poly(A) sequence to a nucleic acid molecule, such as anRNA molecule, e.g. to a premature mRNA. Polyadenylation may be inducedby a so-called polyadenylation signal. This signal is preferably locatedwithin a stretch of nucleotides at the 3′-end of a nucleic acidmolecule, such as an RNA molecule, to be polyadenylated. Apolyadenylation signal typically comprises a hexamer consisting ofadenine and uracil/thymine nucleotides, preferably the hexamer sequenceAAUAAA. Other sequences, preferably hexamer sequences, are alsoconceivable. Polyadenylation typically occurs during processing of apre-mRNA (also called premature-mRNA). Typically, RNA maturation (frompre-mRNA to mature mRNA) comprises the step of polyadenylation.

Restriction site: A restriction site, also termed restriction enzymerecognition site, is a nucleotide sequence recognized by a restrictionenzyme. A restriction site is typically a short, preferably palindromicnucleotide sequence, e.g. a sequence comprising 4 to 8 nucleotides. Arestriction site is preferably specifically recognized by a restrictionenzyme. The restriction enzyme typically cleaves a nucleotide sequencecomprising a restriction site at this site. In a double-strandednucleotide sequence, such as a double-stranded DNA sequence, therestriction enzyme typically cuts both strands of the nucleotidesequence.

RNA, mRNA: RNA is the usual abbreviation for ribonucleic-acid. It is anucleic acid molecule, i.e. a polymer consisting of nucleotides. Thesenucleotides are usually adenosine-monophosphate, uridine-monophosphate,guanosine-monophosphate and cytidine-monophosphate monomers which areconnected to each other along a so-called backbone. The backbone isformed by phosphodiester bonds between the sugar, i.e. ribose, of afirst and a phosphate moiety of a second, adjacent monomer. The specificsuccession of the monomers is called the RNA-sequence. Usually RNA maybe obtainable by transcription of a DNA-sequence, e.g., inside a cell.In eukaryotic cells, transcription is typically performed inside thenucleus or the mitochondria. In vivo, transcription of DNA usuallyresults in the so-called premature RNA which has to be processed intoso-called messenger-RNA, usually abbreviated as mRNA. Processing of thepremature RNA, e.g. in eukaryotic organisms, comprises a variety ofdifferent posttranscriptional-modifications such as splicing,5′-capping, polyadenylation, export from the nucleus or the mitochondriaand the like. The sum of these processes is also called maturation ofRNA. The mature messenger RNA usually provides the nucleotide sequencethat may be translated into an amino-acid sequence of a particularpeptide or protein. Typically, a mature mRNA comprises a 5′-cap, a5′-UTR, an open reading frame, a 3′-UTR and a poly(A) sequence. Asidefrom messenger RNA, several non-coding types of RNA exist which may beinvolved in regulation of transcription and/or translation.

Sequence of a nucleic acid molecule: The sequence of a nucleic acidmolecule is typically understood to be the particular and individualorder, i.e. the succession of its nucleotides. The sequence of a proteinor peptide is typically understood to be the order, i.e. the successionof its amino acids.

Sequence identity: Two or more sequences are identical if they exhibitthe same length and order of nucleotides or amino acids. The percentageof identity typically describes the extent to which two sequences areidentical, i.e. it typically describes the percentage of nucleotidesthat correspond in their sequence position with identical nucleotides ofa reference-sequence. For determination of the degree of identity, thesequences to be compared are considered to exhibit the same length, i.e.the length of the longest sequence of the sequences to be compared. Thismeans that a first sequence consisting of 8 nucleotides is 80% identicalto a second sequence consisting of 10 nucleotides comprising the firstsequence. In other words, in the context of the present invention,identity of sequences preferably relates to the percentage ofnucleotides of a sequence which have the same position in two or moresequences having the same length. Gaps are usually regarded asnon-identical positions, irrespective of their actual position in analignment.

Stabilized nucleic acid molecule: A stabilized nucleic acid molecule isa nucleic acid molecule, preferably a DNA or RNA molecule that ismodified such, that it is more stable to disintegration or degradation,e.g., by environmental factors or enzymatic digest, such as by an exo-or endonuclease degradation, than the nucleic acid molecule without themodification. Preferably, a stabilized nucleic acid molecule in thecontext of the present invention is stabilized in a cell, such as aprokaryotic or eukaryotic cell, preferably in a mammalian cell, such asa human cell. The stabilization effect may also be exerted outside ofcells, e.g. in a buffer solution etc., for example, in a manufacturingprocess for a pharmaceutical composition comprising the stabilizednucleic acid molecule.

Transfection: The term “transfection” refers to the introduction ofnucleic acid molecules, such as DNA or RNA (e.g. mRNA) molecules, intocells, preferably into eukaryotic cells. In the context of the presentinvention, the term “transfection” encompasses any method known to theskilled person for introducing nucleic acid molecules into cells,preferably into eukaryotic cells, such as into mammalian cells. Suchmethods encompass, for example, electroporation, lipofection, e.g. basedon cationic lipids and/or liposomes, calcium phosphate precipitation,nanoparticle based transfection, virus based transfection, ortransfection based on cationic polymers, such as DEAE-dextran orpolyethylenimine etc. Preferably, the introduction is non-viral.

Vector: The term “vector” refers to a nucleic acid molecule, preferablyto an artificial nucleic acid molecule. A vector in the context of thepresent invention is suitable for incorporating or harboring a desirednucleic acid sequence, such as a nucleic acid sequence comprising anopen reading frame. Such vectors may be storage vectors, expressionvectors, cloning vectors, transfer vectors etc. A storage vector is avector, which allows the convenient storage of a nucleic acid molecule,for example, of an mRNA molecule. Thus, the vector may comprise asequence corresponding, e.g., to a desired mRNA sequence or a partthereof, such as a sequence corresponding to the coding sequence and the3′-UTR of an mRNA. An expression vector may be used for production ofexpression products such as RNA, e.g. mRNA, or peptides, polypeptides orproteins. For example, an expression vector may comprise sequencesneeded for transcription of a sequence stretch of the vector, such as apromoter sequence, e.g. an RNA polymerase promoter sequence. A cloningvector is typically a vector that contains a cloning site, which may beused to incorporate nucleic acid sequences into the vector. A cloningvector may be, e.g., a plasmid vector or a bacteriophage vector. Atransfer vector may be a vector, which is suitable for transferringnucleic acid molecules into cells or organisms, for example, viralvectors. A vector in the context of the present invention may be, e.g.,an RNA vector or a DNA vector. Preferably, a vector is a DNA molecule.Preferably, a vector in the sense of the present application comprises acloning site, a selection marker, such as an antibiotic resistancefactor, and a sequence suitable for multiplication of the vector, suchas an origin of replication. Preferably, a vector in the context of thepresent application is a plasmid vector.

Vehicle: A vehicle is typically understood to be a material that issuitable for storing, transporting, and/or administering a compound,such as a pharmaceutically active compound. For example, it may be aphysiologically acceptable liquid, which is suitable for storing,transporting, and/or administering a pharmaceutically active compound.

3′-untranslated region (3′-UTR): Generally, the term “3′-UTR” refers toa part of the artificial nucleic acid molecule, which is located 3′(i.e. “downstream”) of an open reading frame and which is not translatedinto protein. Typically, a 3′-UTR is the part of an mRNA which islocated between the protein coding region (open reading frame (DRF) orcoding sequence (CDS)) and the poly(A) sequence of the mRNA. In thecontext of the invention, the term 3′-UTR may also comprise elements,which are not encoded in the template, from which an RNA is transcribed,but which are added after transcription during maturation, e.g. apoly(A) sequence. A 3′-UTR of the mRNA is not translated into an aminoacid sequence. The 3′-UTR sequence is generally encoded by the gene,which is transcribed into the respective mRNA during the gene expressionprocess. The genomic sequence is first transcribed into pre-mature mRNA,which comprises optional introns. The pre-mature mRNA is then furtherprocessed into mature mRNA in a maturation process. This maturationprocess comprises the steps of 5′ capping, splicing the pre-mature mRNAto excise optional introns and modifications of the 3′-end, such aspolyadenylation of the 3′-end of the pre-mature mRNA and optionalendo-/or exonuclease cleavages etc. In the context of the presentinvention, a 3′-UTR corresponds to the sequence of a mature mRNA, whichis located between the stop codon of the protein coding region,preferably immediately 3′ to the stop codon of the protein codingregion, and the poly(A) sequence of the mRNA. The term “corresponds to”means that the 3′-UTR sequence may be an RNA sequence, such as in themRNA sequence used for defining the 3′-UTR sequence, or a DNA sequence,which corresponds to such RNA sequence. In the context of the presentinvention, the term “a 3′-UTR of a gene”, such as “a 3′-UTR of aribosomal protein gene”, is the sequence, which corresponds to the3′-UTR of the mature mRNA derived from this gene, i.e. the mRNA obtainedby transcription of the gene and maturation of the pre-mature mRNA. Theterm “3′-UTR of a gene” encompasses the DNA sequence and the RNAsequence (both sense and antisense strand and both mature and immature)of the 3′-UTR.

5′-untranslated region (5′-UTR): A 5′-UTR is typically understood to bea particular section of messenger RNA (mRNA). It is located 5′ of theopen reading frame of the mRNA. Typically, the 5′-UTR starts with thetranscriptional start site and ends one nucleotide before the startcodon of the open reading frame. The 5′-UTR may comprise elements forcontrolling gene expression, also called regulatory elements. Suchregulatory elements may be, for example, ribosomal binding sites. The5′-UTR may be post-transcriptionally modified, for example by additionof a 5′-CAP. In the context of the present invention, a 5′-UTRcorresponds to the sequence of a mature mRNA, which is located betweenthe 5′-CAP and the start codon. Preferably, the 5′-UTR corresponds tothe sequence, which extends from a nucleotide located 3′ to the 5′-CAP,preferably from the nucleotide located immediately 3′ to the 5′-CAP, toa nucleotide located 5′ to the start codon of the protein coding region,preferably to the nucleotide located immediately 5′ to the start codonof the protein coding region. The nucleotide located immediately 3′ tothe 5′-CAP of a mature mRNA typically corresponds to the transcriptionalstart site. The term “corresponds to” means that the 5′-UTR sequence maybe an RNA sequence, such as in the mRNA sequence used for defining the5′-UTR sequence, or a DNA sequence, which corresponds to such RNAsequence. In the context of the present invention, the term “a 5′-UTR ofa gene” is the sequence, which corresponds to the 5′-UTR of the maturemRNA derived from this gene, i.e. the mRNA obtained by transcription ofthe gene and maturation of the pre-mature mRNA. The term “5′-UTR of agene” encompasses the DNA sequence and the RNA sequence of the 5′-UTR.By the inventive embodiments such a 5′-UTR may be provided 5′-terminalto the coding sequence. Its length is typically less than 500, 400, 300,25D or less than 200 nucleotides. In other embodiments its length may bein the range of at least ID, 2D, 3D or 4D, preferably up to IDD or 150,nucleotides.

5′Terminal Oligopyrimidine Tract (TOP): The 5′terminal oligopyrimidinetract (TOP) is typically a stretch of pyrimidine nucleotides located inthe 5′ terminal region of a nucleic acid molecule, such as the 5′terminal region of certain mRNA molecules or the 5′ terminal region of afunctional entity, e.g. the transcribed region, of certain genes. Thesequence starts with a cytidine, which usually corresponds to thetranscriptional start site, and is followed by a stretch of usuallyabout 3 to 30 pyrimidine nucleotides. For example, the TOP may comprise3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30 or even more nucleotides. The pyrimidinestretch and thus the 5′ TOP ends one nucleotide 5′ to the first purinenucleotide located downstream of the TOP. Messenger RNA that contains a5′terminal oligopyrimidine tract is often referred to as TOP mRNA.Accordingly, genes that provide such messenger RNAs are referred to asTOP genes. TOP sequences have, for example, been found in genes andmRNAs encoding peptide elongation factors and ribosomal proteins.

TOP motif: In the context of the present invention, a TOP motif is anucleic acid sequence which corresponds to a 5′TOP as defined above.Thus, a TOP motif in the context of the present invention is preferablya stretch of pyrimidine nucleotides having a length of 3-30 nucleotides.Preferably, the TOP motif consists of at least 3 pyrimidine nucleotides,preferably at least 4 pyrimidine nucleotides, preferably at least 5pyrimidine nucleotides, more preferably at least 6 nucleotides, morepreferably at least 7 nucleotides, most preferably at least B pyrimidinenucleotides, wherein the stretch of pyrimidine nucleotides preferablystarts at its 5′-end with a cytosine nucleotide. In TOP genes and TOPmRNAs, the TOP motif preferably starts at its 5′-end with thetranscriptional start site and ends one nucleotide 5′ to the first purinresidue in said gene or mRNA. A TOP motif in the sense of the presentinvention is preferably located at the 5′-end of a sequence, whichrepresents a 5′-UTR, or at the 5′-end of a sequence, which codes for a5′-UTR. Thus, preferably, a stretch of 3 or more pyrimidine nucleotidesis called “TOP motif” in the sense of the present invention if thisstretch is located at the 5′-end of a respective sequence, such as theartificial nucleic acid molecule, the 5′-UTR element of the artificialnucleic acid molecule, or the nucleic acid sequence which is derivedfrom the 5′-UTR of a TOP gene as described herein. In other words, astretch of 3 or more pyrimidine nucleotides, which is not located at the5′-end of a 5′-UTR or a 5′-UTR element but anywhere within a 5′-UTR or a5′-UTR element, is preferably not referred to as “TOP motif”.

TOP gene: TOP genes are typically characterised by the presence of a 5′terminal oligopyrimidine tract. Furthermore, most TOP genes arecharacterized by a growth-associated translational regulation. However,also TOP genes with a tissue specific translational regulation areknown. As defined above, the 5′-UTR of a TOP gene corresponds to thesequence of a 5′-UTR of a mature mRNA derived from a TOP gene, whichpreferably extends from the nucleotide located 3′ to the 5′-CAP to thenucleotide located 5′ to the start codon. A 5′-UTR of a TOP genetypically does not comprise any start codons, preferably no upstreamAUGs (uAUGs) or upstream open reading frames (uDRFs). Therein, upstreamAUGs and upstream open reading frames are typically understood to beAUGs and open reading frames that occur 5′ of the start codon (AUG) ofthe open reading frame that should be translated. The 5′-UTRs of TOPgenes are generally rather short. The lengths of 5′-UTRs of TOP genesmay vary between 20 nucleotides up to 500 nucleotides, and are typicallyless than about 200 nucleotides, preferably less than about 150nucleotides, more preferably less than about 100 nucleotides. Exemplary5′-UTRs of TOP genes in the sense of the present invention are thenucleic acid sequences extending from the nucleotide at position 5 tothe nucleotide located immediately 5′ to the start codon (e.g. the ATG)in the sequences according to SEQ ID NOs:1-1353 of the patentapplication WO 2013/143700, whose disclosure is incorporated herewith byreference. In this context, a particularly preferred fragment of a5′-UTR of a TOP gene is a 5′-UTR of a TOP gene lacking the 5′-TOP motif.The terms “5′-UTR of a TOP gene” or “5′-TOP UTR” preferably refer to the5′-UTR of a naturally occurring TOP gene.

The present invention provides an RNA comprising at least one codingsequence encoding a peptide or protein comprising or consisting of atherapeutic protein, or a fragment or variant of a therapeutic protein.

A “therapeutic protein” as defined herein is typically a peptide or aprotein, which is beneficial for the treatment or prophylaxis of anyinherited or acquired disease or which improves the condition of anindividual. Particularly, therapeutic proteins play a key role in thedesign of new therapeutic agents that could modify and repair geneticdeficiencies, destroy cancer cells or pathogen infected cells, treat orprevent immune system disorders, or treat or prevent metabolic orendocrine disorders, among other functions. For instance, Erythropoietin(EPO), a protein hormone, can be utilized in treating patients witherythrocyte deficiency, which is a common cause of kidney complications.Furthermore, adjuvant proteins are encompassed by therapeutic proteinsand also hormone replacement therapy which is e.g. used in the therapyof women in menopause. In more recent approaches, somatic cells of apatient are used for reprogramming them into pluripotent stem cells,which may substitute the disputed stem cell therapy. Also these proteinsused for reprogramming of somatic cells or used for differentiating ofstem cells are defined herein as therapeutic proteins. Furthermoretherapeutic proteins may be used for other purposes e.g. wound healing,tissue regeneration, angiogenesis, etc.

Therefore, a therapeutic protein as used herein may be a peptide orprotein suitable for use for various purposes including treatment orprevention of various diseases like e.g. infectious diseases, neoplasms(e.g. cancer or tumour diseases), diseases of the blood andblood-forming organs, endocrine, nutritional and metabolic diseases,diseases of the nervous system, diseases of the circulatory system,diseases of the respiratory system, diseases of the digestive system,diseases of the skin and subcutaneous tissue, diseases of themusculoskeletal system and connective tissue, and diseases of thegenitourinary system, independently if they are inherited or acquired.

In the context of the present invention, the term “therapeutic protein”typically comprises peptides as well as proteins. Furthermore, the term“therapeutic protein” may also refer to a peptide or protein comprisinga therapeutic protein as defined herein. For example, the term may referto a polypeptide comprising a therapeutic protein as defined herein,wherein the polypeptide further comprises (preferably at the N-terminalor at the C-terminal side or on both sides of the therapeutic protein) afurther amino acid sequence, which is not derived from a therapeuticprotein. In particular, the term “therapeutic protein” as used hereincomprises precursor proteins comprising a therapeutic protein or fusionproteins comprising a therapeutic protein and another amino acidsequence. Accordingly, the expression “therapeutic protein encoded bythe at least one coding sequence” as used herein may refer to atherapeutic protein as defined herein or to a peptide or proteincomprising a therapeutic protein as defined herein. In other words, a“coding sequence encoding a therapeutic protein” as used herein mayrefer to a coding sequence encoding a therapeutic protein or a fragmentor variant thereof, or to a coding sequence encoding a protein orpeptide comprising a therapeutic protein or a fragment or variantthereof.

The inventors surprisingly found that the RNA according to the inventionis capable of providing sufficient expression of the therapeutic proteinencoded in the at least one coding region upon administration of the RNAto cells or to a patient. In particular, expression levels of thetherapeutic protein can surprisingly be obtained by using the RNA of theinvention which are increased in comparison with the expression levelsobtained by using a reference construct known in the art encoding therespective therapeutic protein.

The RNA according to the present invention preferably comprises at leastone coding sequence encoding a peptide or protein comprising orconsisting of a therapeutic protein, or a fragment or variant thereof,wherein the therapeutic protein is selected from

-   -   (i) therapeutic proteins for use in the treatment of metabolic        or endocrine disorders,    -   (ii) therapeutic proteins for use in the treatment of blood        disorders, diseases of the circulatory system, diseases of the        respiratory system, cancer or tumour diseases, infectious        diseases or immunedeficiencies,    -   (iii) therapeutic proteins used for hormone replacement therapy,    -   (iv) therapeutic proteins used for reprogramming of somatic        cells into pluri- or omnipotent stem cells, and    -   (v) therapeutic proteins selected from adjuvant or        immunostimulating proteins.

Adjuvant or immunostimulating proteins are also encompassed in the termtherapeutic proteins. Adjuvant or immunostimulating proteins may be usedin this context to induce, alter or improve an immune response in anindividual to treat a particular disease or to ameliorate the conditionof the individual. In this context adjuvant proteins may be selectedfrom mammalian, in particular human adjuvant proteins, which typicallycomprise any human protein or peptide, which is capable of eliciting aninnate immune response (in a mammal), e.g. as a reaction of the bindingof an exogenous TLR ligand to a TLR.

Therapeutic proteins for the treatment of blood disorders, diseases ofthe circulatory system, diseases of the respiratory system, cancer ortumour diseases, infectious diseases or immunedeficiencies or adjuvantproteins are typically proteins of mammalian origin, preferably of humanorigin, depending on which animal shall be treated. A human is e.g.preferably treated by a therapeutic protein of human origin.

In a further embodiment therapeutic proteins may be used for hormonereplacement therapy, particularly for the therapy of women in themenopause. These therapeutic proteins are preferably selected fromoestrogens, progesterone or progestins, and sometimes testosterone.

Furthermore, therapeutic proteins may be used for reprogramming ofsomatic cells into pluri- or omnipotent stem cells.

As used herein, the term “therapeutic protein” preferably refers to anyone of the peptides or proteins described herein, more preferably to anyone of the peptides or proteins specified in Table 1 herein. The atleast one coding sequence of the RNA according to the invention thuspreferably encodes a peptide or protein comprising or consisting of atherapeutic protein selected from the peptides or proteins provided inTable 1, or a fragment or variant thereof, whereby the characteristicfeatures of each peptide or protein of the invention is represented bythe formula “01(Peptide or protein or gene) c2(NCBI RefSeq ID)c3(Protein SEQ ID NO) c4(RNA SEQ ID NOs) c5(Related disease, disorder orcondition)”. As Table 1 is depicted as a running text, each entry (i.e.peptide or protein of the invention) is separated by a semicolon and,for ease of readability; each entry is preluded by the number sign (#).

Accordingly, each characteristic feature of the corresponding individualpeptide or protein of the invention is depicted after c1, c2, c3, c4,and c5 in brackets, wherein the abbreviations as disclosed under featurec5 are to be read from the Abbreviation Dictionary for the “Relateddisease, disorder or condition” as shown in Table C, whereby eachabbreviation is depicted with a specific “Related disease, disorder orcondition” in written form, f.e. prostate cancer corresponds to “A”.

According to this, exemplarily the first protein as disclosed in Table 1i.e. “c1(37135 (Sep-01)) c2(NP_443070) c3(1) c4(26115, 39172,52229,13058, 65286) c5(d, c, e, b)” resembles the peptide or proteinshown in Table A.

TABLE A Exemplary depiction from the first entry as disclosed in Table 1(c1, c2, c3, c4, and c5 correspond to the corresponding entry undercolumn 1, column 2, column 3, column 4 and column 5) in accordance withformula “c1(Peptide or protein or gene) c2(NCBI RefSeq ID) c3(ProteinSEG ID NO) c4(RNA SEQ ID NOs) c5(Related disease, disorder orcondition)” and the Abbreviation Dictionary as disclosed in Table C -emphasis added for corresponding entry data (italics, underlined).column 2 column 3 column 4 column 5 column 1 (i.e. feature c2) (i.e.feature c3) (i.e. feature c4) (i.e. feature c5) (i.e. feature c1) NCBIProtein RNA Related disease, Peptide or protein Ref Seq ID SEQ ID NO SEQID NO disorder or condition 37135 (Sep-01) NP_443575 1 26115, 39172,52229 cancer; duchenne 13058, 65286 muscular dystrophy; squamous cellcarcinoma. tongue squamous cell carcinoma

In this context, particularly preferred therapeutic proteins which canbe used inter alis in the treatment of metabolic or endocrine disordersare selected from: 37135 (Sep-01); 37500 (Sep-02); 37865 (Sep-03); 38231(Sep-04); 38596 (Sep-05); 38961 (Sep-06); 3932G (Sep-07); 40057(Sep-09); 40422 (Sep-10); 40787 (Sep-11); 41153 (Sep-12); 41883(Sep-14); A1BG; A1CF; A2M; A2ML1; A4GNT; AAAS; AACS; AADAC; AAGAB; AAKI;AANAT; AARD; AARS2; AARS; AASDH; AASDHPPT; AASS; AATF; AATK; ABAT;ABCA12; ABCA13; ABCA1; ABCA2; ABCA3; ABCA5; ABCA6; ABCA7; ABCA9; ABCB11;ABCB1; ABCB4; ABCB5; ABCB6; ABCB7; ABCB8; ABCB9; ABCC10; ABCC11; ABCC12;ABCC1; ABCC2; ABCC3; ABCC4; ABCC5; ABCC6; ABCC8; ABCC9; ABCD1; ABCD2;ABCD3; ABCD4; ABCE1; ABCF1; ABCF2; ABCG1; ABCG2; ABCG4; ABCG5; ABCG8;ABHD12B; ABHD12; ABHD16A; ABHD17B, ABHD2; ABHDD5; ABHD6; ABI1; ABI2;ABI3BP; ABI3; ABL1; ABL2; ABLIM1; ABLIM2; ABRA; ABR; ABT1; ACAA1; ACAA2;ACACA; ACACB; ACAD1; ACAD8; ACAD9; ACADL; ACADSB; ACADS; ACADVL; ACAN;ACAT1; ACAT2; ACBD3; ACBD4; ACBD5; ACBD6; ACCS; ACD; ACE2; ACE; ACER2;ACER3; ACHE; ACIN1; ACKR1; ACKR2; ACKR3; ACKR4; ACLY; ACMSD; ACO1; ACO2;ACOT13; ACOT1; ACOT2; ACOT9; ACOX1; ACOX2; ACOX3; ACOXL; ACP1; ACP2;ACP5; ACP6; ACPP; ACRBP; ACRE; ACR; ACRV1; ACSBG1; ACSBG2; ACSF3; ACSL1;ACSL3; ACSL5; ACSL6; ACSM1; ACSM2B; ACSM3; ACSS1; ACSS2; ACSS3; ACTA1;ACTA2; ACTB; ACTBL2; ACTC1; ACTG1; ACTG2; ACTL6A; ACTL6B; ACTL8; ACTL9;ACTN1; ACTN2; ACTN3; ACTN4; ACTR1A; ACTR1B; ACTR2; ACTR3B; ACTR3; ACTR5;ACTRT1; ACVR1B; ACVR1C; ACVR1; ACVR2A; ACVR2B; ACVRL1; ACY1; ACY3;ACYP2; ADAD1; ADA; ADAM10; ADAM11; ADAM12; ADAM15; ADAM17; ADAM19;ADAM20; ADAM21; ADAM22; ADAM23; ADAM28; ADAM29; ADAM2; ADAM33; ADAM7;ADAM8; ADAM9; ADAMDEC1; ADAMTS10; ADAMTS12; ADAMTS13; ADAMTS14;ADAMTS15; ADAMTS16; ADAMTS17; ADAMTS18; ADAMTS19; ADAMTS1; ADAMTS20;ADAMTS2; ADAMTS3; ADAMTS4; ADAMTS5; ADAMTS6; ADAMTS7; ADAMTS8; ADAMTS9;ADAMTSL1; ADAMTSL2; ADAMTSL3; ADAMTSL4; ADAMTSL5; ADAP1; ADAP2; ADARB1;ADARB2; ADAR; ADAT2; ADAT3; ADCK3; ADCK4; ADCY10; ADCY1; ADCY2; ADCY3;ADCY5; ADCY6; ADCY7; ADCY8; ADCY9; ADCYAP1; ADCYAP1R1; ADD1; ADD2; ADD3;ADGB; ADGRA1 ; ADGRA2; ADGRA3; ADGRB1; ADGRB2; ADGRB3; ADGRD1; ADGRD2;ADGRE1; ADGRE2; ADGRE5; ADGRF5; ADGRG1; ADGRG2; ADGRG3; ADGRG6; ADGRG7;ADGRL1; ADGRL3; ADGRV1; ADH1A; ADH1B; ADH4; ADH5; ADH6; ADH7; ADHFE1;ADI1; ADIG; ADIPOQ; ADIPOR1; ADIPOR2; ADIRF; ADK; ADM2; ADM; ADNP; ADD;ADDRA1; ADDRA2A; ADDRA2B; ADPGK; ADPRH; ADPRHL1; ADPRHL2; ADRA1A;ADRA1B; ADRA1D; ADRA2A; ADRA2B; ADRA2C; ADRB1; ADRB2; ADRB3; ADRBK1;ADRBK2; ADRM1; ADSL; ADSS; ADSSL1; AUTRP; AEBP2; AEN; AES; AFAP1;AFAP1L1; AFAP1L2; AFF1; AFF2; AFF3; AFF4; AFG3L2; AFM; AFP; AGA; AGAP1;AGAP2; AGAP3; AGAP4; AGBL1; AGBL2; AGBL3; AGBL4; AGER; AGFG1; AGFG2;AGGF1; AGK; AGMO; AG02; AGPAT1; AGPAT2; AGPAT3; AGPAT4; AGPAT9; AGPS;AGR2; AGR3; AGRN; AGRP; AGT; AGTPBP1; AGTR1; AGTR2; AGXT2; AGXT; AHCY;AHCYL2; AHI1; AHNAK; AHR; AHRR; AHSA1; AHSA2; AHSG; AICDA; AIDA; AIF1;AIFM1; AIFM2; AIFM3; AIG1; AIM1; AIM2; AIMP1 ; AIMP2; AIP; AIPL1; AIRE;AJAP1; AJUBA; AK1; AK3; AK7; AK8; AK9; AKAP10; AKAP12; AKAP13; AKAP17A;AKAP1; AKAP2; AKAP3; AKAP4; AKAP5; AKAP6; AKAP7; AKAP9; AKIP1; AKIRIN2;AKNA; AKRIB10; AKR1B1; AKR1C1; AKR1C2; AKR1C3; AKR1C4; AKR1D1; AKR1E2;AKR7A3; AKT1; AKT1S1; AKT2; AKT3; AKTIP; ALAD; ALAS1; ALAS2; ALB; ALCAM;ALDH16A1; ALDH18A1; ALDH1A1; ALDH1A2; ALDH1A3; ALDH1B1; ALDH1L1; ALDH2;ALDH3A1; ALDH3A2; ALDH3B1; ALDH4A1; ALDH5A1; ALDH6A1; ALDH7A1; ALDH9A1;ALDDA; ALDDB; ALD0C; ALG10B; ALG10; ALG11; ALG12; ALG13; ALG1; ALG1L;ALG2; ALG3; ALG8; ALG9; ALKBH1; ALKBH 2; ALKBH3; ALKBH7; ALKBH8; ALK;ALLC; ALMS1; AL0X12B; AL0X12; AL0X15B; AL0X15; AL0X5AP; AL0X5; AL0XE3;ALP1; ALPK1; ALPK2; ALPK3; ALPP; ALPPL2; ALS2CL; ALS2CR12; ALS2; ALX1;ALX4; ALYREF; AMACR; AMBN; AMBP; AMBRA1; AMD1; AMELX; AMELY; AMER1;AMER2; AMER3; AMFR; AMH; AMHR2; AMICA1; AMIG02; AMMECR1; AMN; AM0T;AM0TL1; AMPD2; AMPD3; AMPH; AMT; AWL ANAPC10; ANAPCII; ANAPCI3; ANAPCI;ANAPC2; ANAPC4; ANAPC5; ANAPC7; ANG; ANGPTI; ANGPT2; ANGPT4; ANGPTL1;ANGPTL2; ANGPTL4; ANGPTL6; ANK1; ANK2; ANK3; ANKFN1; ANKFY1; ANKHD1-EIF4EBP3; ANKHD1; ANKH; ANKK1; ANKLE1; ANKLE2; ANKMY1; ANKRD1D;ANKRD11; ANKRD12; ANKRD18A; ANKRD1; ANKRD23; ANKR26; ANKRD28; ANKRD2;ANKRD30A; ANKRD36B; ANKRD36; ANKRD37; ANKRD44; ANKRD45; ANKRS46;ANKRD50; ANKRD55; ANKRD6; ANKRD7; ANKS1A; ANKS1B; ANKS4B; ANK6; ANLN;AN01O; AN01; AN02; AN03; AN04; AN05; AN06; AN07; ANP32A; ANP32B; ANP32D;ANPEP; ANTXR1; ANTXR2; ANXA10; ANXA11; ANXA13; ANXA1; ANXA2; ANXA2R;ANXA3; ANXA4; ANXA5; ANXA6; ANXA7; ANXA8; ANXA8L1; A0AH; A0C1; A0C2;A0C3; A0X1; AP1AR; AP1B1; AP1G1; AP1M1; AP1M2; AP1S1; AP1S2; AP1S3;AP2A1; AP2B1; AP2M1; AP2S1; AP3B1; AP3D1; AP3M2; AP3S1 ; AP3S2; AP4B1;AP4E1; AP4M1; AP4S1; AP5M1; AP5Z1; APAF1; APBA1; APBA2; APBA3; APBB1;APBB1IP; APBB2; APBB3; APC2; APCDD1; APCDD1L; APC; APCS; APEH; APEX1;APEX2; APH1B; API5; APIP; APLN; APLNR; APLP1; APLP2; APDA1BP; AP0A2;AP0A4; AP0A5; AP0BEC1; AP0BEC2; AP0BEC3A_B; AP0BEC3B; AP0BEC3C;AP0BEC3F; AP0BEC3G; AP0BEC3H; AP0B; AP0BR; AP0C1; AP0C2; AP0C3; AP0C4;AP0D; AP0E; AP0F; AP0H; AP0L1; AP0L2; AP0L3; AP0L4; AP0L6; AP0LD1; AP0M;AP00; AP0PT1; APPBP2; APP; APPL1; APPL2; APRT; APTX; ADP10; AQP1; AQP2;AQP3; AQP4; AQP5; AQP6; AQP7; AQP8; AQP9; ARAF; ARAP1; ARAP3; ARC;ARCN1; AREG; ARF1; ARF3; ARF4; ARF6; ARFGAP1; ARFGAP2; ARFGAP3; ARFGEF1;ARFGEF2; ARFGEF3; ARFIP1; ARFRP1; ARG1; ARGLU1; ARHGAP10; ARHGAP11A;ARHGAP11B; ARHGAP15; ARHGAP18; ARHGAP1; ARHGAP20; ARHGAP21; ARHGAP22;ARHGAP23; ARHGAP24; ARHGAP25; ARHGAP26; ARHGAP27; ARHGAP28; ARHGAP30;ARHGAP31; ARHGAP32; ARHGAP35; ARHGAP42; ARHGAP4; ARHGAP5; ARHGAP6;ARHGAP9; ARHGDIA; ARHGDIB; ARHGEF10; ARHGEF10L; ARHGEF11; ARHGEF12;ARHGEF15; ARHGEF16; ARHGEF17; ARHGEF1; ARHGEF25; ARHGEF26; ARHGEF28;ARHGEF2; ARHGEF38; ARHGEF3; ARHGEF4; ARHGEF5; ARHGEF6; ARHGEF7; ARHGEF9;AR; ARID1B; ARID2; ARID3A; ARID3B; ARID4A; ARID4B; ARID5B; ARIH1; ARL11;ARL13A; ARL13B; ARL14EP; ARL14; ARL15; ARL1; ARL2BP; ARL2; ARL3; ARL4A;ARL4C; ARL4D; ARL5A; ARL5B; ARL6; ARLDIP1; ARLDIP5; ARM10; ARMC1; ARMC2;ARMC3; ARMC4; ARMC5; ARMC8; ARMC9; ARMCX1; ARMS2; ARMT1; ARNT2; ARNT;ARNTL2; ARNTL; ARPC1A; ARPC1B; ARPC2; ARPC3; ARPC5; ARPIN; ARPP21; ARR3;ARRB1; ARRB2; ARRDC2; ARRDC3; ARRDC4; ARSA; ARSB; ARSD; ARSE; ARSF;ARSG; ARSH; ARSI; ARSJ; ARSK; ART1; ART3; ART4; ARVCF; ARX; AS3MT;ASAH1; ASAH2; ASAP1; ASAP2; ASB10; ASB13; ASB15; ASB18; ASB1; ASB2;ASB6; ASB7; ASCC1; ASCC2; ASCC3; ASCL1; ASCL2; ASCL4; ASF1A; ASF1B;ASH1L; ASH2L; ASIC1; ASIC2; ASIC3; ASIC4; ASIC5; ASIP; ASL; ASMT; ASMTL;ASNA1; ASNS; ASPA; ASPG; ASPH; ASPM; ASPN; ASPRV1; ASPSCR1; ASRGL1;ASS1; ASTN2; ASUN; ASXL1; ASXL2; ASXL3; ASZ1; ATAD2; ATAD3B; ATAD3C;ATAD5; ATAT1; ATCAY; ATE1; ATF1; ATF2; ATF3; ATF4; ATF5; ATF6B; ATF6;ATF7; ATF7IP; ATG10; ATG12; ATG16L1; ATG2B; ATG3; ATG4A; ATG4B; ATG4C;ATG5; ATG7; ATG9A; ATIC; ATL1; ATL2; ATL3; ATM; ATN1; ATOH1; ATOH7;ATOX1; ATP10A; ATP10B; ATP10D; ATP11A; ATP11AUN; ATP11B; ATP12A;ATP13A3; ATP13A4; ATP1A2; ATP1A3; ATP1A4; ATP1B1; ATP1B2; ATP2A1;ATP2A2; ATP2A3; ATP2B1; ATP2B2; ATP2B3; ATP2B4; ATP2C1; ATP2C2; ATP4A;ATP4B; ATP5A1; ATP5B; ATP5C1; ATP5D; ATP5E; ATP5G1; ATP5G2; ATP5G3;ATP5H; ATP5J2; ATP5J; ATP5L; ATP5O; ATP6AP1; ATP6AP1L; ATP6AP2;ATP6V0A1; ATP6V0A2; ATP6V0A4; ATP6V0C; ATP6V0D1; ATP6V0E1; ATP6V0E2;ATP6V1B1; ATP6V1B2; ATP6V1C1; ATP6V1D; ATP6V1E1; ATP6V1F; ATP6V1G1;ATP6V1G2; ATP6V1G3; ATP7A; ATP7B; ATP8A1; ATP8A2; ATP8B1; ATP8B3;ATP8B4; ATP9B; ATPAF2; ATRAID; ATR; ATRIP; ATRN; ATRNL1; ATRX; ATXN10;ATXN1; ATXN1L; ATXN2; ATXN2L; ATXN3; ATXN7; ATXN7L3B; AUH; AURKA; AURKB;AURKC; AUTS2; AVEN; AVP; AVPI1; AVPR1A; AVPR1B; AVPR2; AWAT1; AXDND1;AXIN1; AXIN2; AXL; AZGP1; AZI2; AZIN1; AZIN2; AZU1; B2M; B3GALNT1;B3GALNT2; B3GALT2; B3GALT4; B3GALT5; B3GALTL; B3GAT1; B3GAT2; B3GAT3;B3GNT2; B3GNT3; B3GNT5; B3GNT6; B3GNT8; B3GNTL1; B4GALNT1; B4GALNT2;B4GALNT3; B4GALT1; B4GALT3; B4GALT4; B4GALT5; B4GALT6; B4GALT7; B4GAT1;B9D1; B9D2; BAALC; BAAT; BABAM1; BACE1; BACE2; BACH1; BACH2; BAD; BAG1;BAG3; BAG4; BAG5; BAG6; BAIAP2L1; BAIAP3; BAK1; BAMBI; BANF1; BANK1;BANP; BAP1; BARD1; BARHL1; BARX1; BARX2; BASP1; BATF2; BATF; BAX; BAZ1A;BAZ1B; BAZ2A; BAZ2B; BBC3; BBIP1; BBDX1; BBS10; BBS12; BBS1; BBS2; BBS4;BBS5; BBS7; BBS9; BBX; BCAM; BCAN; BCAP29; BCAP31; BCAR1; BCAS1 ; BCAS3;BCAS4; BCAT1; BCAT2; BCCIP; BCDIN3D; BCHE; BCKDHA; BCKDHB; BCKDK; BCL10;BCL11A; BCL11B; BCL2A1; BCL2; BCL2L10; BCL2L11; BCL2L12; BCL2L13;BCL2L14; BCL2L1; BCL2L2; BCL2L2-PABPN1; BCL3; BM; BCE; BCL7A; BCL7B;BCL7C; BCL9L; BCLAF1; BC01; BC02; BC0R; BCDRL1; BCR; BCS1L; BDH1; BDH2;BDKRB1; BDKRB2; BDNF; BDP1; BEAN1; BEGAIN; BEND3; BEND4; BEST1; BEST2;BET1; BET1L; BEX1; BEX2; BEX4; BFAR; BFSP1; BFSP2; BGLAP; BGN; BHLHA15;BHLHA9; BHLHB9; BHLHE22; BHLHE23; BHLHE40; BHLHE41; BHMT2; BHMT; BICC1;BICD1; BICD2; BID; BIN1; BIN2; BIN3; BIRC2; BIRC3; BIRC5; BIRC6; BIRC7;BIVM; BLCAP; BLID; BLK; BLMH; BLM; BLNK; BLOC1S2; BLOC1S3; BLOC1S4;BLOC1S5; BLOC1S6; BLVRA; BLVRB; BLZF1; BMF; BMI1; BMP10; BMP15; BMP1;BMP2; BMP2K; BMP3; BMP4; BMP5; BMP6; BMP7; BMP8B; BMPER; BMPR1A; BMPR1B;BMPR2; BMS1; BMX; BNC1; BNC2; BNIP1; BNIP2; BNIP3; BNIP3L; BNIPL; HOC;BODIL2; BOK; BOLA3; BOLL; BOP1; BORA; BPGM; BPIFA1; BPIFA2; BPIFA3;BPIFB1; BPIFB2; BPIFC; BPI; BPNT1; BPTF; BPY2; BRAF; BRAP; BRAT1; BRCA1;BRCA2; BRCC3; BRD1; BRD2; BRD3; BRD4; BRD7; BRD8; BRE; BRF1; BRF2;BRI3BP; BRI3; BRINP1; BRINP2; BRINP3; BRIP1; BRK1; BRMS1; BRMS1L; BRS3;BRSK1; BRSK2; BRWD1; BRWD3; BSCL2; BSG; BSN; BSPH1; BSPRY; BST1; BST2;BSX; BTBD10; BTBD11; BTBD16; BTBD1; BTBD2; BTBD3; BTBD9; BTC; BTD; BTF3;BTG1; BTG2; BTG3; BTG4; BTK; BTLA; BTN1A1; BTN2A1; BTN2A2; BTN3A1;BTN3A2; BTN3A3; BTNL2; BTRC; BUB1B; BUB1; BUB3; BUD13; BUD31; BVES;BYSL; BZRAP1; BZW1; C10orf107; C10orf10; C10orf113; C10orf11; C10orf2;C10orf32; C10orf35; C10orf54; C10orf67; C10orf82; C10orf88; C10orf90;C11orf21; C11orf30; C11orf53; C11orf65; C11orf68; C11orf73; C11orf74;C11orf80; C11orf87; C11orf95; C12orf10; C12orf42; C12orf43; C12orf50;C12orf57; C12orf5; C12orf65; C12orf66; C12orf75; C12orf77; C14or166;C14orf177; C14orf1; C15orf32; C15orf41; C15orf48; C15orf53; C15orf59;C16orf72; C16orf74; C16orf78; C16orf95; C17orf51; C17orf53; C17orf64;C17orf96; C18orf54; C18orf8; C19orf12; C19orf18; C19orf24; C19orf26;C19orf33; C19orf40; C19orf45; C19orf48; C19orf57; C19orf68; C1D;C1GALT1C1; C1GALT1; C1orf106; C1orf109; C1orf110; C1orf112; C1orf115;C1orf127; C1orf141; C1orf167; C1orf204; C1orf226; C1orf228; C1orf27;C1orf61; C1orf86; V1Qb; C1QBP; C1QL1; C1QL3; C1QTNF1; C1QTNF3; C1QTNF5;C1QTNF6; C1QTNF7; C1QTNF9B-AS1; C1R; C1RL; C1S; C20orf194; C20orf196;C20orf27; C20orf85; C21orf2; C21orf33; C21orf59; C21orf62; C21orf91;C22orf29; C2CD3; C2CD4A; C2CD4B; C2CD5; C2; C2orf16; C2orf40; C2orf43;C2orf47; C2orf57; C2orf61; C3AR1; C3; C3orf17; C3orf18; C3orf20;C3orf35; C3orf56; C3orf58; C3orf67; C3orf79; C4A; C4B_ 2; C4B; C4BPA;C4BPB; C4orf22; C4orf26; C4orf27; C4orf32; C4orf33; C4orf36; C4orf48;C4orf51; C5AR1; C5AR2; C5; C5orf22; C5orf30; C5orf34; C5orf38; C5orf42;C5orf63; C6; C6orf106; C6orf10; C6orf15; C6orf25; C6orf47; C6orf48;C6orf89; C7; C7orf49; C7orf57; C7orf60; C7orf62; C7orf65; C7orf69;C7orf72; C8orf34; C8orf37; C8orf46; C8orf48; C8orf4; C8orf86; C9;C9orf106; C9orf135; C9orf152; C9orf156; C9orf170; C9orf171; C9orf3;C9orf43; C9orf66; C9orf72; C9orf85; C9orf91; C9orf9; CAI1O; CA11; CA12;CA13; CA1; CA2; CA3; CA4; CA5A; CA6; CA8; CAB39; CAB39L; CABIN1;CABLES1; CABP2; CABP4; CABS1; CABYR; CACNA1A; CACNA1B; CACNA1C; CACNA1D;CACNA1E; CACNA1F; CACNA1G; CACNA1H; CACNA1I; CACNA1S; CACNA2D1;CACNA2D2; CACNA2D3; CACNA2D4; CACNB1; CACNB2; CACNB3; CACNB4; CACNG2;CACNG3; CACNG4; CACNG5; CACNG6; CACUL1; CACYBP; CAD; CADM1; CADM2;CADM3; CADM4; CADPS2; CADPS; CAGE1; CALB1; CALB2; CALCA; CALCB;CALCOC01; CALCOC02; CALCR; CALCRL; CALD1; CALHM1; CALHM2; CALHM3; CALM2;CALML3; CALML5; CALN1; CALR3; CALR; CALU; CALY; CAMK1D; CAMK1G; CAMK1;CAMK2A; CAMK2B; CAMK2D; CAMK2G; CAMK4; CAMKK1; CAMKK2; CAMKMT; CAMLG;CAMP; CAMSAP1; CAMSAP2; CAMTA1; CAND1; CAND2; CANT1; CANX; CAP1; CAP2;CAPG; CAPN10; CAPN13; CAPN14; CAPN1; CAPN2; CAPN3; CAPN5; CAPN6; CAPN7;CAPN9; CAPNS1; CAPRIN1; CAPRIN2; CAPS2; CAPS; CAPSL; CAPLA2; CAPLA3;CARD10; CARD11; CARD14; CARD16; CARD6; CARD8; CARD9; CARF; CARKD; CARM1;CARS; CARTPT; CASC1; CASC3; CASC4; CASC5; CASD1; CASK; CASP1; CASP14;CASP1; CASP2; CASP3; CASP4; CASP5; CASP6; CASP7; CASP8AP2; CASP8; CASP9;CASQ1; CASR; CASS4; CAST; CASZ1; CAT; CATSPER1; CATSPER2; CAV1; CAV2;CAV3; CBFA2T2; CBFA2T3; CBFB; CBLB; CBL; CBLL1; CBLN1; CBLN2; CBLN4;CBR1; CBR3; CBR4; CBS; CBX1; CBX2; CBX3; CBX4; CBX5; CBX6; CBX7; CBX8;CBY1; CC2D1A; CC2D1B; CC2D2A; CCAR1; CCAR2; CCBE1; CCBL1; CCDC101;CCDC102B; CCDC103; CCDC105; CCDC108; CCDC114; CCDC115; CCDC121; CCDC122;CCDC129; CCDC130; CCDC134; CCDC136; CCDC140; CCDC141; CCDC148; CCDC151;CCDC167; CCDC169- SOHLH2; CCDC170; CCDC171; CCDC175; CCDC176; CCDC178;CCDC180; CCDC181; CCDC185; CCDC22; CCDC28A; CCDC39; CCDC3; CCDC40;CCDC42B; CCDC42; CCDC50; CCDC54; CCDC60; CCDC62; CCDC63; CCDC65; CCDC66;CCDC67; CCDC68; CCDC6; CCDC78; CCDC80; CCDC83; CCDC85A; CCDC86; CCDC88A;CCDC88C; CCDC8; CCDC91; CCDC94; CCDC97; CCHCR1; CCKAR; CCKBR; CCK;CCL11; CCL13; CCL14; CCL15; CCL16; CCL17; CCL18; CCL19; CCL1; CCL20;CCL21; CCL22; CCL23; CCL24; CCL25; CCL26; CCL27; CCL28; CCL2; CCL3;CCL3L3; CCL4; CCL4L1; CCL4L2; CCL5; CCL7; CCL8; CCM2; CCNA1; CCNA2;CCNB1; CCNB2; CCNB3; CCNC; CCND1; CCND2; CCND3; CCNDBP1; CCNE1; CCNE2;CCNF; CCNG1; CCNG2; CCNH; CONI; CCNJ; CCNJL; CONK; CCNL1; CCNL2; CCND,CCNT1; CCNY; CCP110; CCR10; CCR1; CCR2; CCR3; CCR4; CCR5; CCR6; CCR7;CCR8; CCR9; CCRL2; CCRN4L; CCSER1; CCS; CCT2; CCT3; CCT4; CCT5; CCT6A;CCT6B; CCT7; CD109; CD14; CD151; CD163; CD163L1; CD164; CD177; CD180;CD19; CD1A; CD1B; CD1C; CD1D; CD1E; CD200; CD200R1; CD207; CD209; CD226;CD22; CD244; CD247; CD248; CD24; CD274; CD276; CD27; CD28; CD2AP;CD300A; CD300C; CD300LF; CD302; CD320; CD33; CD34; CD36; CD37; CD38;CD3D; CD3EAP; CD3E; CD3G; CD40; CD40LG; CD44; CD46; CD47; CD48; CD4;CD55; CD59; CD5; CD5L; CD63; CD68; CD69; CD6; CD72; CD74; CD79A; CD79B;CD7; CD80; CD81; CD82; CD83; CD84; CD86; CD8A; CD8B; CD93; CD96; CD99;CD9; CDADC1; CDAN1; CDC123; CDC14A; CDC14B; CDC16; CDC20B; CDC23;CDC25A; CDC25B; CDC25C; CDC27; CDC34; CDC37; CDC37L1; CDC42BPA;CDC42BPB; CDC42BPG; CDC42EP1; CDC42EP3; CDC42SE2; CDC45; CDC5L; CDC6;CDC73; CDC7; CDCA2; CDCA3; CDCA5; CDCA7; CDCA7L; CDCP1; CH10; CH11;CDH13; CDH15; CDH16; CDH17; CDH18; CDH19; CDH1; CDH20; CDH22; CDH23;CDH26; CDH2; CDH3; CDH4; CDH5; CDH6; CDH7; CDH8; CDH9; CDHR1; CDHR2;CDHR3; CDHR5; CDIPT; CDK10; CDK11B; CDK12; CDK13; CDK14; CDK15; CDK16;CDK17; CDK18; CDK19; CDK1; CDK20; CDK2AP1; CDK2AP2; CDK2; CDK3; CDK4;CDK5; CDK5R1; CDK5R2; CDK5RAP1; CDK5RAP2; CDK5RAP3; CDK6; CDK7; CDK8;CDK9; CDKAL1; CDKL1; CDKL2; CDKL3; CDKL4; CDKL5; CDKN1A; CDKN1B; CDKN1C;CDKN2A; CDKN2A1P; CDKN2B; CDKN2C; CDKN2D; CDKN3; CDNF; CD01; CD0N; CDR1;CDR2; CDS2; CDT1; CDV3; CDX1; CDX2; CDX4; CDY1B; CDY2B; CDYL2; CDYL;CEACAM16; CEACAM19; CEACAM1; CEACAM21; CEACAM3; CEACAM4; CEACAM5;CEACAM6; CEACAM7; CEACAM8; CEBPA; CEBPB; CEBPD; CEBPE; CEBPG; CEBPZ;CECR1; CECR2; CELA1; CELA3B; CELF1; CELF2; CELF4; CELF5; CELF6; CEL;CELSR1; CELSR3; CEMIP; CEMP1; CEND1; CENPA; CENPB; CENPC; CENPE; CENPF;CENPH; CENPJ; CENPK; CENPN; CENPD; CENPO; CENPU; CENPV; CENPW; CEP112;CEP120; CEP128; CEP131; CEP135; CEP152; CEP162; CEP164; CEP170; CEP192;CEP19; CEP250; CEP290; CEP41; CEP55; CEP57; CEP63; CEP68; CEP72; CEP76;CEP83; CEP85L; CEP89; CER1; CERK; CERKL; CERS1; CERS2; CERS3; CERS4;CERS6; CES1; CES2; CES3; CETN1; CETN2; CETN3; CETP; CFAP126; CFAP36;CFAP44; CFAP52; CFAP53; CFAP57; CFAP58; CFAP61; CFAP69; CFAP97; CFB;CFC1B; CFC1; CFD; CFDP1; CFH; CFHR1; CFHR2; CFHR3; CFHR4; CFHR5; CFI;CFL1; CFL2; CFLAR; CFP; CFTR; CGA; CGB1; CGB2; CGB5; CGB7; CCN; CGNL1;CGRRF1; CH25H; CHAC1; CHAD; CHAF1A; CHAF1B; CHAMP1; CHAT; CHCHD10;CHCHD1; CHCHD3; CHCHD5; CHCHD6; CHCHD7; CHD1; CHD2; CHD3; CHD4; CHD6;CHD7; CHD8; CHDH; CHEK1; CHEK2; CHERP; CHFR; CHGA; CHGB; CHI3L1; CHIL1;CHIC2; CHIT1; CHKA; CHKB; CHL1; CHM; CHML; CHMP1A; CHMP1B; CHMP2B;CHMP3; CHMP4A; CHMP4B; CHMP4C; CHMP5; CHN1; CHN2; CHDDL; CHORDC1; CHP1;CHP2; CHPF; CHPT1; CHRAC1; CHRD; CHRDL1; CHRFAM7A; CHRM1; CHRM2; CHRM3;CHRM4; CHRM5; CHRNA10; CHRNA1; CHRNA2; CHRNA3; CHRNA4; CHRNA5; CHRNA6;CHRNA7; CHRNB1; CHRNB2; CHRNB3; CHRNB4; CHRND; CHRNE; CHRNG; CHST10;CHST11; CHST12; CHST13; CHST14; CHST15; CHST1; CHST2; CHST3; CHST4;CHST5; CHST6; CHST8; CHST9; CHSY1; CHSY3; CHTF18; CHTOP; CHURC1; CIAO1;CIAPIN1; CIB1; CIB2; CIC; CIDEB; CIDEC; CIITA; CILP2; CILP; CINP; CIPC;CIR1; CIRBP; CIRH1A; CISD1; CISD2; CISH; CITED1; CITED2; CIT; CIZ1;CKAP2; CKAP2L; CKAP4; CKAP5; CKB; CKLF; CKM; CKMT1A; CKMT1B; CKMT2;CKS18; CKS2; CLASP1; CLASP2; CLCA2; CLCA4; CLCF1; CLC; CLCN1; CLCN2;CLCN3; CLCN4; CLCN5; CLCN6; CLCN7; CLCNK8; CLDN10; CLDN11; CLDN14;CLDN15; CLDN16; CLDN18; CLDN1; CLDN23; CLDN2; CLDN5; CLDN6; CLDN7;CLDN8; CLDN9; CLEC10A; CLEC11A; CLEC12A; CLEC14A; CLEC16A; CLEC18;CLEC2A; CLEC2B; CLEC2D; CLEC2L; CLEC3B; CLEC4A; CLEC4C; CLEC4D; CLEC4E;CLEC4G; CLEC4M; CLEC5A; CLEC6A; CLEC7A; CLEC9A; CLECL1; CLGN; CLIC1;CLIC3; CLIC5; CLIC6; CLINT1; CLIP1; CLIP2; CLK1; CLK2; CLLU1; CLMN;CLMP; CLN3; CLN5; CLN6; CLN8; CLNK; CLNS1A; CLOCK; CLP1; CLPP; CLPS;CLPTM1; CLPTM1L; CLRN1; CLSPN; CLSTN1; CLSTN2; CLTA; CLTC; CLTCL1;CLUAP1; CLU; CLUL1; CLVS1; CLYBL; CMA1; CMAS; CMC1; CMC2; CMC4; CMIP;CMKLR1; CMPK2; CMSS1; CMTM3; CMTM5; CMTM7; CMTM8; CMTR1; CMTR2; CMYA5;CNBD1; CNBP; CNDP1; CNDP2; CNGA1; CNGA3; CNGB1; CNGB3; CNIH3; CNKSR1;CNKSR2; CNKSR3; CNN1; CNN2; CNNM1; CNNM2; CNNM4; CNOT1; CNOT2; CNOT3;CNOT4; CNOT6; CNOT6L; CNOT7; CNOT8; CNP; CNPY2; CNPY3; CNR1; CNR2;CNRIP1; CNST; CNTF; CNTFR; CNTLN; CNTN1; CNTN2; CNTN3; CNTN4; CNTN5;CNTN6; CNTNAP1; CNTNAP2; CNTNAP3; CNTNAP4; CNTNAP5; CNTRL; CNTROB; COA1;COA5; COASY; COBL; COBLL1; COCH; COG1; COG2; COG3; COG4; COG5; COG6;COG7; COG8; COIL; COL1DA1; COL11A1; COL11A2; COL12A1; COL13A1; COL14A1;COL15A1; COL16A1; COL17A1; COL18A1; COL1A1; COL1A2; COL2DA1; COL21A1;COL22A1; COL23A1; COL24A1; COL25A1; COL26A1; COL27A1; COL28A1; COL2A1;COL3A1; COL4A1; COL4A2; COL4A3BP; COL4A3; COL4A4; COL4A5; COL4A6;COL5A1; COL5A2; COL5A3; COL6A1; COL6A2; COL6A3; COL6A5; COL7A1; COL8A1;COL8A2; COL9A1; COL9A2; COL9A3; COLCA1; COLCA2; COLEC10; COLEC11;COLEC12; COLGALT2; COLQ; COMMD1D; COMMD1; COMMD3-BM11; COMMD5; COMMD7;COMP; ENT; COPA; COPB1; COPB2; COPE; COPG2; CONS; COPS2; COPS3; COPS4;COPS5; COPS6; COPS7A; COPS8; COPZ2; COQ2; COQ3; COQ4; COQ5; COQ6; COQ7;COQ9; CORIN; CORD1A; CORD1B; CORD1C; CORO2A; CORO2B; CORO6; CORO7;CORO7-PAM16; COTL1; COX10; COX11; COX14; COX15; COX16; COX17; COX18;COX19; COX4I1; COX4I2; COX5A; COX5B; COX6A1; COX6A2; COX6B1; COX6C;COX7A1; COX7A2; COX7A2L; COX7B2; COX7B; COX7C; COX8A; CPA1; CPA2; CPA3;CPA4; CPA6; CPAMD8; CPB1; CPB2; CPD; CPEB1; CPEB3; CPEB4; CPED1; CPE;CP; CPLX1; CPLX2; CPLX3; CPLX4; CPM; CPN1; CPN2; CPNE1; CPNE2; CPNE3;CPNE4; CPNE7; CPNE8; CPO; CPOX; CPPED1; CPQ; CPS1; CPSF1; CPSF2; CPSF3;CPSF3L; CPSF4; CPSF6; CPSF7; CPT1A; CPT1B; OPT1C; CPVL; CPXCR1; CPZ;CR1; CR2; CRABP1; CRABP2; CRACR2A; CRADD; CRAMP1L; CRAT; CRB1; CRB2;CRB3; CRBN; CROP; CRCT1; CREB1; CREB3; CREB3L1; CREB3L2; CREB3L3;CREB3L4; CREB5; CREBBP; CREBRF; CRERF; CREG1; CRELD1; CRELD2; CREM;CRHBP; CRH; CRHR1; CRHR2; CRIM1; CRIP2; CRIP3; CRIPAK; CRIPT; CRISP1;CRISP2; CRISP3; CRISPLD1; CRISPLD2; CRK; CRKL; CRLF1; CRLF2; CRLF3;CRLS1; CRMP1; CRNKL1; CRNN; CROCE; ERN; CRP; CRTACI1; CRTAM; CRTAP;CRTC1; CRTC2; CRTC3; CRX; CRY1; CRY2; CRYAB; CRYBA1; CRYBA2; CRYBA4;CRYBB1; CRYBB2; CRYBB3; CRYGB; CRYGC; CRYGD; CRYGS; CRYL1; CRYM; CRYZL1;CSAD; CSAG3; CSE1L; CSF1R; CSF2; CSF2RA; CSF2RB; CSF3; CSGALNACT1;CSGALNACT2; CSH1; CSH2; CSHL1; CS; CSK; CSMD1; CSMD12; CSMD3;CSN1S1CSN2; CSN3; CSNK1AI; CSNK1D; CSNK1G3; CSNK2A1; CSNK2A2; CSNK2B;CSPG4; CSPG5; CSPP1; CSRNP1; CSRNP3; CSRP1; CSRP2BP; CSRP2; CSRP3; CST1;CST2; CST3; CST4; CST5; CST6; CST7; CST8; CST9; CST9L; CSTA; CSTB;CSTF1; CSTF2; CSTF2T; CSTL1; CT45A1; CT55; CT83; CTAG1A; CTAG2; CTAGE1;CTAGE5; CTBP1; CTBP2; CTC1; CTCF; CTCFL; CTOP1; CTDSP1; CTOSP2; CTDSPL;CTF1I; CTGF; CTHRC1; CT1F; CTLA4; CTNNA1; CTNNA2; CTNNA3; CTNNAL1;CTNNB1; CTNNBL1; CTNND1; CTNND2; CTRS; CTPS1; CTR9; CTRB1; CTRB2; CTRL;CTRL; CTSA; CTSB; CTSC; CTSD; CTSE; CTSF; CTSG; CTSH; CTSL; CTSO; CTSV;CTSW; CTSZ; CTTNBP2; CTTN; CTU1; CTXN3; CUBN; CUEDC1; CUEDC2; CUL1;CUL2; CUL3; CUL4A; CUL4B; CUL5; CUL7; CUL9; CUTA; CUX1; CUX2; CUZD1;CWC22; CWC27; CWF19L1; CWF19L2; CWH43; CX3CL1; CX3CR1; CXADR; CXCL10;CXCL11; CXCL12; CXCL13; CXCL14; CXCL16; CXCL17; CXCL1; CXCL2; CXCL3;CXCL5; CXCL6; CXCL8; CXCL9; CXCR1; CXCR2; CXCR3; CXCR4; CXCR5; CXCR6;CXorf36; CXorf66; CXorf67; CXXC1; CXXC4; CYB5B1D2; CYB561; CYB5A; CYB5B;CYB5R3; CYB5R4; CYBA; CYBB; CYBRD1; CYC1; CYCS; CYFIP1; CYFIP2; CYGB;CYLC1; CYLC2; CYLD; CYP11A1; CYP11B1; CYP11B2; CYP17A1; CYP19A1; CYP1A1;CYP1A2; CYP1B1; CYP21A2; CYP24A1; CYP26A1; CYP26B1; CYP26C1; CYP27A1;CYP27B1; CYP27C1; CYP2A13; CYP2A6; CYP2A7; CYP2B6; CYP2C18; CYP2C19;CYP2C8; CYP2C9; CYP2D6; CYP2E1; CYP2F1; CYP2R1; CYP2S1; CYP2U1; CYP2W1;CYP39A1; CYP3A43; CYP3A4; CYP3A5; CYP3A7-CYP3A51P; CYP3A7; CYP46A1;CYP4A11; CYP4B1; CYP4F11; CYP4F12; CYP4F22; CYP4F2; CYP4F3; CYP4F8;CYP4V2; CYP5IA1; CYP7A1; CYP7B1; CYP8B1; CYS1; CYSLTR1; CYTH1; CYTH3;CYTIP; CYTL1; CYYR1; D2HGDH; DAAM1; DAAM2; DAB2; DAB2IP; DACH1; DACH2;DACT1; DACT2; DACT3; DAD1; DAG1; DAND5; DADA; DAD; DAP3; DAP; DAPK1;DAPK2; DAPK3; DARS2; DARS; DAW1; DAZ1; DAZ2; DAZ3; DAZ4; DAZAP1; DAZAP2;DAZL; DBF4; OH; DBI; DBN1; DBNL; DBP; DBR1; DBX1; DCAF12; DCAF13;DCAF17; DCAF4; DCAF5; DCAF6; DCAF7; DCAF8; DCANP1; DCBLD1; DCBLD2; DCC;DCDC2C; DCDC2; DCD; DCHS1 ; DCHS2; DCK; DCLK1; DCLK2; DCLK3; DCLRE1A;DCLRE1C; DCN; DCP1A; DCP1B; DCPS; DCST1; DCST2; DCSTAMP; DCTD; DCT;DCTN1; DCTN2; OCTN3; DCTN4; DCTN5; DCTN6; DCUN1D1; DCX; DCXR; DDAH1;DDAH2; DDB1; DDB2; DDC; DDHD1; DDHD2; DDI1; DDIAS; DDIT3; DDIT4; DDIT4L;DDN; DDD; DDR1; DDR2; DORGK1; DDT; DDTL; DDX10; DDX11; DDX17; DDX18;DDX19A; DDX1; DDX21; DDX25; DDX27; DDX31; DDX39A; DDX39B; DDX3X; DDX3Y;DDX41; DDX42; DDX43; DDX46; DDX4; DDX50; DDX51; DDX52; DDX53; DDX54;DDX56; DDX58; DDX59; DDX5; DDX60; DDX6; DEAF1; DEL1; DECR1; DEDD; DEF6;DEFA1B; DEFA3; DEFA4; DEFA5; DEFA6; DEFB103B; DEFB104B; DEFB105A;DEFB106A; DEFB108B; DEFB112; DEFB125; DEFB126; DEFB1; DEFB4A; DEGS1;DEGS2; DEK; DENND1A; DENND1B; DENND2A; DENND4A; DENR; DEPDC1B; DEPDC5;DEPTOR; DERA; DERL1; DERL2; DERL3; DES; DESI2; DEXI; DFFB; DFNA5;DFNB31; DFNB59; DGAT1; DGAT2; DGCR2; DGCH6L; DGCR8; DGKA; DGKB; DGKD;DGKE; DGKG; DGKH; DGKI; DGKK; DGKQ; DGKZ; DGUPL; DHCR7; DHDH; DHFR;DHFRL1; DHH; DHODH; DHPS; DHRS11; DHRS2; DHRS4; DHRS7C; DHRS9; DHTKD1;DHX15; DHX16; DHX32; DHX34; DHX36; DHX38; DHX40; DHX58; DHX8; DHX9;DIABLO; DIAPH1; DIAPH2; DIAPH3; DICER1; DIDD1; DIEXF; DIP2A; DIP2B;DIP2C; DIRAS1; DIRAS2; DIRC1; DIRC2; DIS3; DIS3L2; DIS3L; DISC1; DISP1;DIXDC1; DKC1; DKK1; OKK2; DKK3; OKK4; DKKL1; DLAT; DLC1; DLD; DLEC1;DLEU7; DLG1; DLG2; DLG3; DLG4; DLG5; DLGAP1; DLGAP2; DLGAP3; DLGAP5;DLK1; DLL1; DLL3; DLL4; DLST; DLX1; DLX2; DLX3; DLX4; DLX5; DLX6; DMBT1;DMC1; DMD; DMGDH; DMKN; DMP1; DMPK; DMBT1; DMRT2; DMRT3; DMRTA1; DMTF1;DMTN; DMWD; DMXL1; DMXL2; ONA2; DNAAF1; DNAAF2; DNAAF3; DNAAF5; DNAH11;DNAH12; DNAH17; DNAH1; DNAH2; DNAH3; DNAH5; DNAH6; DNAH7; DNAH8; DNAH9;DNAI1; DNAI2; DNAJA1; DNAJA2; DNAJA3; DNAJB11; DNAJB13; DNAJB1; DNAJB2;DNAJB5; DNAJB6; DNAJB7; DNAJB8; DNAJB9; DNAJC10; DNAJC12; DNAJC13;DNAJC14; DNAJC15; DNAJC18; DNAJC19; DNAJC1; DNAJC27; DNAJC28; DNAJC2;DNAJC3; DNAJC5; DNAJC7; DNAL1; DNASE1; DNASE1L2; DNASE1L3; DNASE2B;DNASE2; DND1; DNER; DNHD1; DNLZ; DNM1; DNM1L; DNM2; DNM3; DNMBP; DNMT1;DNMT3A; DNMT3B; DNMT3L; DNPEP; DNTT; DOC2A; DOC2B; DOCK10; DOCK11;DOCK1; DOCK2; DOCK3; DOCK4; DOCK5; DOCK6; DOCK7; DOCK8; DOCK9; DOHH;DOK1; DOK2; DOK3; DOK4; DOK5; DOK6; DOK7; DDLK; DONSON; DOPEY2; OOT1L;DPAGT1; DPCD; DPCR1; DPEP1; DPEP2; DPEP3; DPF1; DPF3; DPH1; DPH3; DPH6;DPH7; DPM1; DPM2; DPM3; DPP10; DPP3; DPP4; DPP6; DPP7; DPP8; DPP9;DPPA2; DPPA3; DPPA4; DPT; DPY19L2; DPY19L3; DPY30; DPYS; DPYSL2; DPYSL3;DPYSL4; DPYSL5; DRAM1; DRAP1; DRC1; DRD1; DRD2; DRD3; DRD4; DRD5; DRG1;DRGX; DROSHA; DRP2; DSC1; DSC2; DSC3; DSCAM; DSCAML1; DSCC1; DSCR4; DSE;DSEL; DSG1 ; DSG2; DSG3; DSG4; DSP; DSPP; DST; DSTN; DSTYK; DTD1; DTHD1;DTL; DTNA; DTNB; DTNBP1; DTX1; DTX2; DTX3; DTX4; DTYMK; DUOX1; DUOX2;DUOXA1; DUOXA2; DUPDB1; DUPD1; DUS2; DUSP10; DUSP11; DUSP12; DUSP13;DUSP14; DUSP15; DUSP16; DUSP18; DUSP1; DUSP21; DUSP22; DUSP23; DUSP27;DUSP28; DUSP2; DUSP3; DUSP4; DUSP5; DUSP6; DUSP7; DUSP8; DUSP9; DUT;DUX4; DVL2; DVL3; DXD; DYM; DYNAP; DYNC1H1; DYNC1I1; DYNC1I2; DYNC1LI1;DYNC2H1; DYNLL1; DYNLL2; DYNLRB1; DYNLT1; DYNLT3; DYRK1A; DYRK1B; DYRK2;DYRK3; DYSF; DYX1C1; DZIP1; E2F1; E2F3; E2F4; E2F5; E2F6; E2F7; E2F8;E4F1; EAF1; EAF2; EARS2; EBAG9; EBF1; EBF2; EBF3; EBF4; EBI3; EBP; EBPL;ECD; ECE2; ECEL1; ECHDC1; ECHDC3; ECHS1; ECI1; ECI2; ECSCR; ECSIT; ECT2;EDA2R; EDA; EDARADD; EDAR; EDC4; EDEM1; EDIL3; EDN1; EDN3; EDNRA; EDNRB;EEA1; EED; EEF1A1; EEF1A2; EEF1B2; EEF1D; EEF1E1; EEF1G; EEF2; EEFSEC;EFCABI1; EFCAB1; EFEMP1; EFEMP2; EFHB; EFHC1; EFHC2; EFHD1; EFNA1;EFNA2; EFNA3; EFNA4; EFNA5; EFNB1; EFNB2; EFNB3; EFR3A; EFR3B; EFS;EFTUD1; EFTUD2; EGF; EGFLD; EGFL7; EGFL8; EGFLAM; EGFR; EGLN1; EGLN2;EGLN3; EGR1; EGR2; EGR3; EGR4; EHBP1; EHD1; EHD2; EHD3; EHD4; EHF;EHHADH; EHMT1; EHMT2; EI24; EID1; EIF1AD; EIF1AX; EIF1AY; EIF1; EIF2A;EIF2AK1; EIF2AK2; EIF2AK3; EIF2AK4; EIF2B1; EIF2B2; EIF2B3; EIF2B4;EIF2B5; EIF2S1; EIF2S2; EIF2S3; EIF3A; EIF3B; EIF3C; EIF3E; EIF3F;EIF3H; EIF3J; EIF3K; EIF3M; EIF4A1; EIF4A2; EIF4A3; EIF4B; EIF4E2;EIF4E3; EIF4EBP1; EIF4EBP2; EIF4EBP3; EIF4E; EIF4ENIF1; EIF4G1; EIF4G2;EIF4H; EIF5A2; EIF5A; EIF5; EIF6; ELAC1; ELAC2; ELANE; ELAVL1; ELAVL2;ELAVL3; ELAVL4; ELF1; ELF2; ELF3; ELF4; ELF5; ELK1; ELK3; ELK4; ELL2;ELL; ELMO1; ELMO2; ELMOD1; ELMOD2; ELMOD3; ELMSAN1; ELN; ELDF1; ELDVL2;ELDVL4; ELDVL5; ELDVL6; ELDVL7; ELP2; ELP3; ELP4; ELP6; ELSPBP1; EMB;EMC10; EMC2; EMC3; EMC7; EMC8; EMCN; EMD; EME1; EMG1; EMILIN1; EMILIN2;EMILIN3; EML1; EML2; EML4; EML5; EML6; EMP1; EMP2; EMX1; EMX2; EN1; EN2;ENAH; ENAM; ENC1; ENDOG; ENDOU; ENDOV; ENGASE; ENG; ENHO; ENO2; ENO3;ENO4; ENOPH1; ENOSF1; ENOX1; ENOX2; ENPEP; ENPP1; ENPP2; ENPP3; ENPP5;ENPP7; ENTHD2; ENTPD1 ; ENTPD2; ENTPD4; ENTPD5; ENTPD6; ENTPD7; EOGT;EOMES; EP300; EP400; EPAS1; EPB41L1; EPB41L2; EPB41L3; EPB41L4A;EPB41L4B; EPB42; EPC1; EPC2; EPCAM; EPDR1; EPG5; EPGN; EPHA1; EPHA3;EPHA4; EPHA5; EPHA6; EPHA7; EPHB1; EPHB3; EPHB4; EPB5; EPHX1; EPHX2;EPHX3; EPM2A; EPM2AIP1; EPN1; EPO; EPOR; EPPIN; EPPIN-WFDC6; EPPK1;EPRS; EPS15L1; EPS8; EPS8L2; EPSTI1; EPX; EPYC; ERAL1; ERAP1; ERAP2;ERAS; ERBB2; ERBB2IP; ERBB3; ERBB4; ERC1; ERC2; ERCC1; ERCC2; ERCC3;ERCC4; ERCC5; ERCC6; ERCC6L2; ERCC6-PGBD3; ERCC8; EREG; ERF; ERG;ERGIC1; ERGIC2; ERGIC3; ERI3; ERICH5; ERICH6B; ERLEC1; ERLIN1; ERLIN2;ERMAP; ERMARD; ERMP1; ERN1; ERN2; ERO1LB; ERO1L; ERP29; ERP44; ERV3-1;ERVW-1; ESAM; ESCO1; ESCO2; ESD; ESF1; ESM1; ESPL1; ESPN; ESR1; ESR2;ESRP1; ESRP2; ESRRA; ESRRB; ESRRG; ESX1; ESYT1; ESYT2; ESYT3; ETAA1;ETF1; ETFA; ETFB; ETFDH; ETHE1; ETNK1; ETNK2; ETNPPL; ETS1; ETS2; ETV1;ETV3; ETV4; ETV5; ETV6; ETV7; EVA1A; EVA1C; EVC2; EVC; EVI2A; EVI2B;EVI5; EVL; EVPL; EVX1; EVX2; EWSR1; EXD2; EXD3; EXO1; EXOC1; EXOC2;EXOC3L1; EXOC3L2; EXOC4; EXOC5; EXOC7; EXOG; EXOSC1; EXOSC2; EXOSC3;EXOSC4; EXOSC5; EXOSC6; EXOSC7; EXOSC8; EXPH5; EXT1; EXT2; EXTL2; EXTL3;EYA1; EYA2; EYA4; EYS; EZH1; EZH2; EZR; F10; F11; F11R; F12; F13A1;F13B; F2; F2R; F2RL1; F2RL2; F2RL3; F5; F7; F8; F9; FA2H; FAAH2; FABP1;FABP2; FABP4; FABP5; FABP6; FABP7; FABP9; FADD; FADS1; FADS2; FADS3;FAF2; FAHD2A; FAH; FAIM2; FAIM3; FAM102A; FAM103A1; FAM105A; FAM107A;FAM107B; FAM109A; FAM110A; FAM110B; FAM110C; FAM111B; FAM114A1; FAM120B;FAM120C; FAM124B; FAM126A; FAM129A; FAM129B; FAM134B; FAM135A; FAM135B;FAM136A; FAM13A; FAM13C; FAM149A; FAM150B; FAM155A; FAM160B1; FAM161A;FAM163A; FAM163B; FAM167A; FAM168A; FAM168B; FAM169B; FAM170A; FAM172A;FAM173B; FAM174A; FAM175A; FAM175B; FAM177A1; FAM177B; FAM178A; FAM178B;FAM179B; FAM180A; FAM184A; FAM184B; FAM187B; FAM188A; FAM188B; FAM189B;FAM193B; FAM196A; FAM196B; FAM198B; FAM19A1; FAM19A2; FAM19A4; FAM19A5;FAM204A; FAM205A; FAM20A; FAM20B; FAM20C; FAM210B; FAM213A; FAM214A;FAM216A; FAM220A; FAM227B; FAM32A; FAM3A; FAM3B; FAM3C; FAM3D; FAM46A;FAM46D; FAM49A; FAM49B; FAM50B; FAM53B; FAM57A; FAM58A; FAM60A; FAM63B;FAM64A; FAM65B; FAM69C; FAM71F1; FAM71F2; FAM72B; FAM78B; FAM81B;FAM83A; FAM83B; FAM83D; FAM83H; FAM84A; FAM84B; FAM89A; FAM92A1; FAM92B;FAM9B; FAN1; FANCA; FANCB; FANCC; FANCD2; FANCE; FANCF; FANCG; FANCI;FANCL; FANCM; FANKI; FAP; FARI; FARPI; FABP2; FARS2; FARSA; FAS; FASLG;FASN; FASTKD2; FASTK; FATI; FAT2; FAT3; FAT4; FATE1; FAU; FBF1; FBL;FBLIM1; FBLN1; FBLN2; FBLN5; FBN1; FBN2; FBN3; FBP1; FBP2; FBRS; FBXL15;FBXL17; FBXL19; FBXL20; FBXL2; FBXL3; FBXL4; FBXL5; FBXL7; FBXO10;FBXO11; FBXO15; FBXO17; FBXO18; FBXO28; FBXO30; FBXO31; FBXO32; FBXO33;FBXO38; FBXO3; FBXO40; FBXO47; FBXO4; FBXO5; FBXO7; FBXO8; FBXD9;FBXW11; FBXW4; FBXW7; FBXW8; FCAR; FCER1A; FCER1G; FCER2; FCGBP; FCGR2A;FCGR2B; FCGR3A; FCGR3B; FCGRT; FCHO1; FCHO2; FCHSD2; FCN1; FCN2; FCRL1;FCRL2; FCRL3; FCRL4; FCRL5; FCRL6; FCRLA; FCRLB; FDFT1; FDPS; FDX1;FDX1L; FDXR; FECH; FEM1A; FEM1B; FEM1C; FEN1; FERD3L; FER; FERMT1;FERMT2; FERMT3; FES; FEV; FEZ1; FEZ2l FEZF1; FEZF2; FFAR1; FFAR2; FFAR3;FFAR4; FGA; FCB; FGD1; FGD2; FGD3; FGD4; FGD5; FGD6; FGF10; FGF11;FGF12; FGF13; FGF14; FGF16; FGF17; FGF18; FGF19; FGF1; FGF20; FGF21;FGF23; FGF2; FGF3; FGF4; FGF5; FGF6; FGF7; FGF8; FGF9; FGFBP1; FGFBP2;FGFBP3; FGFR1; FGFR10P2; FGFR10P; FGFR2; FGFR3; FGFR4; FGFRL1; FGG;FGGY; FGL1; FGL2; FGR; FHDC1; FH; FHIT; FHL1; FHL2; FHL5; FFOD1; FHOD3;FIBP; FIG4; FIGF; FIGLA; FIGN; FILIP1; FILIP1L; FIP1L1; FIS1; FITM1;FITM2; FJX1; FKBP10; FKBP11; FKBP14; FKBP15; FKBP1A; FKBP1B; FKBP2;FKBP3; FKBP4; FKBP5; FKBP6; FKBP7; FKBP8; FKBP9; FKBPL; FKRP; FKTN;FLAD1; FLCN; FLG2; FLG; FLI1; FLII; FLNA; FLNB; FLNC; FLOT1; FLOT2;FLRT2; FLRT3; FLT1; FLT3; FLT3LG; FLT4; FLVCR1; FLVCR2; FMN1; FMN2;FMNL1; FMNL2; FMNL3; FMO1; FMO2; FMO3; FMO4; FMOD; FMR1; FN1; FN3K;FN3KRP; FNBP1; FNDC1; FNDC3A; FNDC3B; FNDC4; FNTA; FNTB; FOCAD; FOLH1;FOLR1; FOLR2; FOLR3; FOPNL; FOSB; FOS; FOSL1; FOSL2; FOXA1; FOXA2;FOXA3; FOXB1; FOXC1; FOXC2; FOXD1; FOXD2; FOXE1; FOXF2; FOXG1; FOXH1;FOXI1; FOXJ1; FOXJ2; FOXK1; FOXK2; FOXL1; FOXL2; FOXM1; FOXN1l FOXN2;FOXN3; FOXO1; FOXO3; FOXO4; FOXP1; FOXP2; FOXP3; FOXP4; FOXQ1; FOXR1;FOXR2; FOXRED1; FPGS; FPR1; FPR2; FPR3; FRAS1; FRAT1; FRAT2; FREM1;FREM2; FREM3; FRG1; FRG2; FRK; FRMD3; FRMD4A; FRMD4B; FRMD5; FRMD6;FRMD7; FRMPD1; FRMPD2; FRMPD4; FRRS1L; FRS2; FRS3; FRY; FRYL; FRZB;FSBP; FSCB; FSCN1; FSCN2; FSD1; FSD1L; FSD2; FSHB; FSHR; FSIP1; FST;FSTL1; FSTL3; FSTL4; FSTL5; FTCD; FTH1; FTL; FTMT; FTD; FTSJ1; FTSJ2;FTSJ3; FUBP1; FUBP3; FUCA1; FUCA2; FUNDC1; FUNDC2; FURIN; FUS; FUT10;FUT11; FUT1; FUT2; FUT3; FUT4; FUT5; FUT6; FUT7; FUT8; FUT9; FUZ; FXN;FXR1; FXR2; FXYD1; FXYD2; FXYD3; FXYD5; FXYD6; FYB; FYCO1; FYN; FZD10;FZD1; FZD2; FZD3; FZD5; FZD6; FZD7; FZD8; FZD9; FZR1; GOS2; G2E3; G3BP1;G6PC2; G6PC3; G6PC; G6PD; GAA; GAB1; GAB2; GAB3; GABARAP; GABARAPL1;GABARAPL2; GABBR1; GABBR2; GABPA; GABPB1; GABRA1; GABRA2; GABRA3;GABRA4; GABRA5; GABRA6; GABRB1; GABRB2; GABRB3; GABRE; GABRG1; GABRG2;GABRG3; GABRP; GABRD; GABRR1; GABRR2; GAD1; GAD2; GADD45B; GADD45G;GADD45GIP1; GADL1; GAGE10; GAGE1; GAK; GALC; GAL; GALK1; GALK2; GALM;GALNS; GALNT12; GALNT13; GALNT14; GALNT15; GALNT18; GALNT1; GALNT2;GALNT3; GALNT4; GALNT5; GALNT6; GALNT7; GALNT8; GALNT9; GALNTL6; GALP;GALR1; GALR2; GALR3; GALT; GAMT; GANAB; GANC; GAN; GAP43; GAPDH; GAPDHS;GAR1; GAREM; GARNL3; GARS; GART; GAS1; GAS2; GAS2L1; GAS6; GAS7; GAS8;GAST; GATA1; GATA2; GATA3; GATA4; GATA5; GATA6; GATAD1; GATAD2A;GATAD2B; GATB; GATM; GBA2; GBA; GBAS; GBE1; GBF1; GBGT1; GBX1; GBX2;GCA; GCC1; GCDH; GCFC2; GCG; GCGR; GCH1; GCHFR; GC; GCK; GCKR; GCLC;GCM1; GCM2; GCN1L1; GCNT1; GCNT2; GCNT3; GCNT7; GCOM1; GCSAM; GCSAML;GCSH; GDA; GDAP1; GDE1; GDF10; GDF11; GDF15; GDF1; GDF2; GDF3; GDF5;GDF6; GDF7; GDF9; GD11; GD12; GDNF; GDPD3; GDPD5; GEM; GEMIN2; GEMIN4;GEMIN6; GEN1; GET4; GFAP; GFER; GFI1B; LFI1; GFM1; GFPT1; GFPT2; GFRA1;GFRA2; GFRA3; GFRA4; GGA1; GGA3; GGACT; GGCT; GGCX; GGH; GGNBP2; GGN;GGPS1; GGT1; GGT2; GGT5; GGTLC1; GH1; GH2; GHITM; GHRH; GHR; GHRHR;GHRL; GHSR; GIDS; GIF; GIGYF1; GIGYF2; GIMAP5; GIMAP7; GIMAP8; GIN1;GINS1; GINS2; GIPC1; GIPC3; GIP; GIPR; GIT1; GIT2; GJA1; GJA3; GJA8;GJB1; GJB2; GJB6; GJC1; GJC2; GJC3; GJD2; GJD3; GK; GKN1; GKN2; GLA;GLB1; GLCCI1; GLCE; GLDC; GLDN; GLE1; GLG1; GLI1; GLI2; GLI3; GLIPR1;GLIPR2; GLIS2; GLIS3; GLMN; GLO1; GLOD4; GLP1R; GLP2R; GLRA1; GLRA2;GLRA3; GLRB; GLRX2; GLRX3; GLRX5; GLRX; GLS2; GLS; GLT1D1; GLT6D1;GLT8D1; GLTSCR1; GLTSCR2; GLUD1; GLUD2; GLUL; GLYAT; GLYATL3; GLYCTK;GM2A; GMCL1; GMDS; GMFB; GMFG; GMIP; GML; GMNN; GMPPA; GMPPB; GMPR2;GMPR; GMPS; GNA11; GNA12; GNA13; GNA14; GNA15; GNAI1; GNAI2; GNAL;GRAD1; GNAQ; GRAS; GNAT1; GNAT3; GRAZ; GNB1L; GNB2L1; GNB3; GNB4; GNB5;GNE; GNG10; GNG11; GNG2; GNG4; GNG7; GNG8; GNGT1; GNGT2; GNL1; GNL3;GNL3L; GNLY; GNMT; GNPAT; GNPDA1; GNPDA2; GNPTAB; GNPTG; GNRH1; GNRH2;GNRHR; GNS; GOLGA1; GOLGA2; GOLGA3; GOLGA4; GOLGA5; GOLGA8B; GOLGB1;GOLM1; GOLPH3; GOLT1A; GOLT1B; GON4L; GOPC; GORAB; GORASP1; GORASP2;GOSR1; GOSR2; GOT2; GP1BA; GP1BB; GP2; GP5; GP6; GP9; GPA33; GPAA1;GPALPP1; GPAM; GPANK1; GPAT2; GPATCH1; GPATCH2; GPATCH2L; GPATCH8;GPBAR1; GPC1; GPC2; GPC3; GPC4; GPC5; GPC6; GPCPD1; GPD1; GPD1L; GPD2;GPER1; GPHA2; GPHN; GPIHBP1; GP1; GRGPKOW; GPLD1; GPM; GPM; GPN1; GPNMB;GPR101; GPR119; GPR12; GPR132; GPR135; GPR137C; GPR139; GPR143; GPR148;GPR149; GPR150; GPR151; GPR152; GPR153; GPR155; GPR156; GPR158; GPR15;GPR160; GPR161; GPR162; GPR11; GPR174; GPR176; GPR179; GPR17; GPR180;GPR182; GPR183; GPR19; GPR1; GPR20; GPR22; GPR26; GPR34; GPR35; GPR37;GPR37L1; GPR39; GPR4; GPR50; GPR52; GPR55; GPR65; GPR68; GPR6; GPR75;GPR78; GPRB83; GPR87; GPRASP1; GPRC5A; GPRC5B; GPRC5C; GPRC5D; GPRC6A;GPRIN1; GPRIN2; GPRIN3; GPS2; GPSM1; GPSM2; GPSM3; GPT2; GPT; GPX5;GRAMD1B; GRAMD3; GRAMD4; GRAP2; GRAP; GRASP; GRB10; GRB14; GRB2; GRB7;GREB1; GREM1; GREM2; GRHL1; GRHL2; GRHPR; GRIA1; GRIA2; GRIA3; GRIA4;GRID1; GRID2; GRIK1; GRIK2; GRIK4; GRIK5; GRIN1; GRIN2A; GRIN2B; GRIN2C;GRIN2D; GRIN3A; GRIN3B; GRINA; GRIP1; GRK1; GRK4; GRK5; GRK6; GRK7;GRM1; GRM2; GRM3; GRM4; GRM5; GRM6; GRM7; GRM8; GRN; GRPEL1; GRP; GRPR;GRSF1; GRXCR1; GRXCR2; GSC2; GSC; GSDMA; GSDMB; GSDMC; GSDMD; GSE1;GSG1L; GSK3A; GSK3B; CSN; GSPT1; GSPT2; GSR; CSS; GSTA1; GSTA2; GSTA4;GSTA5; GSTCD; GSTK1; GSTM3; GSTO1; GSTO2; GSTP1; GSTT1; GSTT2B; GSTT2;GSTL1; GSX1; GSX2; GTDC1; GTF2A1; GTF2A1L; GTF2A2; GTF2E1; GTF2E2;GTF2F1; GTF2F2; GTF2H1; GTF2H2C2; GTF2H2C; GTF2H2; GTF2H3; GTF2H4;GTF2H5; GTF2I; GTF2IRD1; GTF2IRD2; GTF3A; GTF3C1; GTPBP1; GTPBP3;GTPBP4; GTSF1; GUCA1A; GUCA1B; GUCD1; GUCY1A2; GUCY1A3; GUCY1B3; GUCY2C;GUCY2D; GUCY2F; GUK1; GULP1; GUSH; GYG1; GYG2; GYLTL1B; GYPA; GYPB;GYPC; GYPE; GYS1; GYS2; GN1; GLMA; GLMB; GLMH; GLMK; GLMM; H1FO; H1FX;H2AFJ; H2AFX; H2AFY2; H2AFY; H2AFL; H2BFWT; H3F3B; HAAD; HABP2; HABP4;HACD1; HACD2; HACD4; HACE1; HACL1; HADHA; HADHB; HADH; HAGH; HAL; HAMP;HAND1; HAND2; HAO1; HAO2; HAP1; HAPLN1; HAPLN4; HARS2; HARS; HAS1; HAS2;HAS3; HAT1; HAVCR1; HAVCR2; HAX1; HBA2; HBB; HD; HBE1; HBEGF; HBG1;HBG2; HBM; HBP1; HBD1; HBS1L; HZ; HCAR1; HCAR2; HCAR3; HCCS; HCFC1;HCFC2; HCK; HCLS1; HCN1; HCN2; HCN3; HCN4; HCRT; HCRTR2; HCST; HDAC10;HDAC11; HDAC1; HDAC2; HDAC3; HDAC4; HDAC5; HDAC6; HDAC7; HDAC8; HDAC9;HDC1; HDDC2; HDGF; HDGFL1; HDGFRP3; HDHD1; HDLBP; HEATR1; HEATR3;HEATR5B; HEATR6; HEBP1; HEBP2; HECA; HECTD2; HECTD4; HECW1; HECW2; HEG1;HELLS; HELQ; HELT; HELZ2; HELZ; HEMGN; HEPACAM; HEPH; HEPN1; HERC1;HERC2; HERC3; HERC5; HERC6; HERPUD1; HES1; HES2; HES6; HES7; HESX1;HEXA; HEXB; HEXDC; HEXIM1; HEY1; HEY2; HFE; HFM1; HGD; HGFAC; HGF; HGH1;HGS; HGSNAT; HHAT; HHATL; HHEX; HHIP; HHIPL1; HHLA1; HHLA2; HIAT1;HIBADH; HIBCH; HIC1; HIC2; HID1; HIF1A; HIF1AN; HIF3A; HIGD1A; HIGD1C;HIGD2A; HILPDA; HINFP; HINT1; HINT2; HIP1; HIP1R; HIPK1; HIPK2; HIPK3;HIRA; HIRIP3; HIST1H1A; HIST1H1B; HIST1H1C; HIST1H1D; HIST1H1E;HIST1H1T; HIST1H2AE; HIST1H2AH; HIST1H2BG; HIST1H2BH; HIST1H2BM;HIST1H3G; HIST1H4D; HIST3H3; HIVEP1; HIVEP2; HJURP; HK1; HK2; HK3;HKDC1; HLA-A; HLA-B; HLA-C; HLA-DMA; HLA-DMB; HLA-DOA; HLA-DOB;HLA-DPA1; HLA-DPB1; HLA-DQA1; HLA-DQA2; HLA-DQB1; HLA-DQB2; HLA-DRA;HLA-DRB1; HLA-DRB3; HLA-DRB4; HLA-DRB5; HLA-E; HLA-F; HLA-G; HLCS; HLF;HLTF; HLX; HM13; HMBOX1; HMBS; HMCN1; HMG20A; HMG20B; HMGA1; HMGA2;HMGB1; HMGB2; HMGB3; HMGCR; HMGCS1; HMGN1; HMGN4; HMGN5; HMGXB3; HMGXB4;HMHA1; HMMR; HMDX1; HMDX2; HMP19; HMSD; HMX1; HN1; HN1L; HNF1A; HNF1B;HNF4A; HNF4G; HNMT; HNRNPAQ; HNRNPA1; HNRNPA2B1; HNRNPA3; HNRNPAB;HNRNPC; HNRNPD; HNRNPDL; HNRNPF; HNRNPH1; HNRNPH2; HNRNPK; HNRNPL;HNRNPM; HNRNPR; HNRNPU; HNRNPUL1; HOGA1; HOMER1; HOMER2; HOMER3; HOMEZ;HOOK2; HOOK3; HOPX; HORMAD2; HOXA10; HOXA11; HOXA13; HOXA1; HOXA2;HOXA3; HOXA4; HOXA5; HOXA6; HOXA7; HOXA9; HOXB13; HOXB1; HOXB2; HOXB3;HOXB4; HOXB5; HOXB6; HOXB7; HOXB8; HOXB9; HOXC10; HOXC11; HOXC12;HOXC13; HOXC4; HOXC5; HOXC6; HOXC8; HOXC9; HOXD10; HOXD11; HOXD12;HOXD13; HOXD1; HOXD3; HOXD4; HOXD8; HOXD9; HP1BP3; HPCAL1; HPD; HPGD;HPGDS; HP; HPN; HPR; HPRT1; HPS1; HPS3; HPS4; HPS5; HPS6; HPSE2; HPSE;HPX; HRAS; HRASLS; HRC; HRC; HRH1; HRH2; HRH3; HRH4; HR; HRK; HRNR;HRSP12; HSIBP3; HS3ST1; HS3ST2; HS3ST3A1; HS3ST3B1; HS3ST4; HS3ST5;HS3ST6; HS6ST1; HS6ST2; HS6ST3; HSBP1; HSD11B1; HSD11B1L; HSD17B2;HSD17B10; HSD17B11; HSD17B12; HSD17B13; HSD17B14; HSD17B1; HSD17B2;HSD17B3; HSD17B4; HSD17B6; HSD17B7; HSD17B8; HSD3B1; HSD3B7; HSDL1;HSDL2; HSF1; HSF2; HSF4; HSF5; HSFY2; HSH2D; HSPHAA1; HSPHAB1; HSP90B1;HSPA12A; HSPA12B; HSPA13; HSPA14; HSPA1A; HSPA1L; HSPA2; HSPA4; HSPA4L;HSPA5; HSPA6; HSPA8; HSPA9; HSPB1; HSPA2; HSPB3; HSPB6; HSPB7; HSPB8;HSPB9; HSPBAP1; HSPBP1; HSPD1; HSPE1; HSPG2; HSPH1; HTATIP2; HTN1; HTN3;HTR1A; HTR1B; HTR1E; HTR1F; HTR2A; HTR2B; HTR2C; HTR3A; HTR3B; HTR3C;HTR3D; HTR3E; HTR4; HTR5A; HTR7; HTRA1; HTRA2; HTRA3; HTRA4; HTT; HUNK;HUS1B; HUS1; HUWE1; HVCN1; HYAL1; HYAL2; HYAL3; HYAL4; HYDIN; HYKK;HYLS1; HYOU1; HYPM; IAPP; IARS2; IARS; IBA57; IBSP; IBTK; ICA1; ICAM1;ICAM2; ICAM3; ICAM4; ICAM5; ICE1; ICE2; ICK; ICMT; ICOS; ICOSLG; ID1;ID2; ID4; IDE; IDH1; IDH2; IDH3B; IDNK; IDO1; IDO2; IDS; IDUA; IER2;IER3; IER3IP1; IER5; IFF01; IFF02; IFI16; IFI27; IFI30; IFI35; IFI44;IFIH1; IFIT1; IFIT2; IFIT3; IFIT5; IFITM1; IFITM2; IFITM3; IFITM5;IFNA10; IFNA13; IFNA14; IFNA15; IFNA17; IFNA1; IFNA21; IFNA2; IFNA4;IFNA5; IFNA6; IFNA7; IFNA8; IFNAR1; IFNAR2; IFNB1; IFNE; IFNG; IFNGR1;IFNGR2; IFNK; IFNL1; IFNL2; IFNL3; IFNW1; IFRD1; IFT122; IFT14D; IFT172;IFT27; IFT43; IFT57; IFT74; IFT80; IFT88; IGBP1; IGDCC3; IGF1; IGF1R;IGF2BP1; IGF2BP2; IGF2BP3; IGF2; IGF2R; IGFALS; IGFBP1; IGFBP2; IGFBP3;IGFBP4; IGFBP5; IGFBP6; IGFBP7; IGFBPL1; IGFL1; IGFLR1; IGHMBP2; IGJ;IGLL1; IGSF10; IGSF11; IGSF1; IGSF5; IGSF6; IGSF8; IHH; IKBKAP; IKBKB;IKBKE; IKBKG; IK; IKZF1; IKZF2; IKZF3; IKZF4; IL10; IL10RA; IL10RB;IL11; IL11RA; IL12A; IL12B; IL12RB1; IL13; IL13RA1; IL13RA2; IL15;IL15RA; IL16; IL17A; IL17B; IL17C; IL17D; IL17F; IL17RA; IL17RB; IL17RC;IL17RD; IL17RE; IL17REL; IL18BP; IL18; IL18R1; IL18RAP; IL19; IL1A;IL1B; IL1F10; IL1R1; IL1R2; IL1RAP; IL1RAPL1; IL1RAPL2; IL1RL1; IL1RL2;IL1RN; IL20; IL20RA; IL20RB; IL21; IL21R; IL22; IL22RA2; IL23A; IL23R;IL24; IL25; IL25; IL27; IL27RA; IL2; IL2RA; IL2RB; IL2RG; IL31; IL3IRA;IL32; IL33; IL34; IL35A; IL3513; IL35G; IL3fiRN; IL37; IL3; IL3RA; IL4;IL4I1; IL4R; IL5; IL5RA; IL6; IL6R; IL6ST; IL7; IL7R; IL9; IL9R; ILDR1;ILDR2; ILF2; ILF3; ILK; IMMP1L; IMMP2L; IMMT; IMP3; IMPA1; IMPA2;IMPACT; IMPAD1; IMPDH1; IMPDH2; IMPG1; IMPG2; INADL; INA; INCENP; INF2;ING1; ING2; ING3; ING4; ING5; INHA; INHBA; INHBB; INHBC; INHBE; INO80B;INO80D; INO80; INPP; INPP4A; INPP4B; INPP5A; INPP5B; INPP5D; INPP5E;INPP5F; INPP5K; INPPL1; INSC; INS; INSIG1; INSIG2; INS-IGF2; INSL3;INSL4; INSL6; INSM1; INSM2; INSR; INSRR; INTS12; INTS1; INTS2; INTS3;INTS4; INTS5; INTS6; INTS7; INTS8; INTU; INVS; IP6K1; IP6K2; IP6K3;IPCEF1; IPMK; IPO011; IPO13; IPO7; IPO8; IPO9; IQCB1; IQCG; IQCH; IQCJ;IQCJ; IQCJ-SCHIP1; IQCK; IQGAP1; IQGAP2; IQGAP3; IQSEC1; IQSEC2; IQSEC3;IRAK1BP1; IRAK1; IRAK2; IRAK3; IRAK4; IREB2; IRF1; IRF2BP2; IRF2BPL;IRF2; IRF3; IRF4; IRF5; IRF6; IRF7; IRF8; IRF9; IRG1; IRGM; IRS1; IRS2;IRS4; IRX1; IRX2; IRX3; IRX4; IRX5; ISCU; ISG20; ISL1; ISM1; ISM2; ISPD;IST1; ISX; ISYNA1; ITCH; ITFG1; ITFG3; ITGA10; ITGA11; ITGA1; ITGA2B;ITGA2; ITGA3; ITGA4; ITGA5; ITGA6; ITGA7; ITGA8; ITGA9; ITGAD; ITGAE;ITGAL; ITGAM; ITGAV; ITGAX; ITGB1BP1 ; ITGB1; ITGB2; ITGB3; ITGB4;ITGB5; ITGB6; ITGB7; ITGB8; ITGBL1; ITIH1; ITIH2; ITIH3; ITIH4; ITIH5;ITK; ITLN1; ITLN2; ITM2A; ITM2B; ITM2C; ITPA; ITPK1; ITPKA; ITPKC;ITPR1; ITPR2; ITPR3; ITSN1; ITSN2; IVD; IVL; IVNS1ABP; IYD; IZUMO1;JADE1; JADE2; JAG1; JAG2; JAGN1; JAK2; JAK3; JAKMIP1; JAKMIP2; JAKMIP3;JAM2; JAM3; JARID2; JAZF1; JDP2; JMJD1C; JMJD6; JMY; JPH2; JPH3; JPH4;JRK; JSRP1; JTB; JUNB; JUND; JUP; KAL1; KALRN; KANK1; KANK2; KANK4;KANSL1; KANSL3; KARS; KAT2A; KAT2B; KAT5; KAT6A; KAT6B; KAT7; KAT8;KATNA1; KATNAL2; KATNB1; KAZALD1; KAZN; KBTBD11; KBTBD13; KBTBD8; KCMF1;KCNA1; KCNA4; KCNA5; KCNA6; KCNA7; KCNAB1; KCNAB2; KCNAB3; KCNB1; KCNB2;KCNC1; KCNC2; KCNC3; KCND2; KCNE1; KCNE2; KCNE3; KCNE4; KCNE5; KCNG3;KCNG4; KCNH1; KCNH2; KCNH3; KCNH4; KCNH5; KCNH6; KCNH7; KCNH8; KCNIP1;KCNIP2; KCNIP3; KCNIP4; KCNJ10; KCNJ11; KCNJ12; KCNJ13; KCNJ14; KCNJ15;KCNJ16; KCNJ18; KCNJ1; KCNJ2; KCNJ3; KCNJ4; KCNJ5; KCNJ6; KCNJ8; KCNJ9;KCNK10; KCNK12; KCNK15; KCNK17; KCNK18; KCNK1; KCNK2; KCNK3; KCNK5;KCNK6; KCNK9; KCNMA1; KCNMB1; KCNMB2; KCNMB3; KCNMB4; KCNN1; KCNN2;KCNN3; KCNN4; KCNQ1I; KCNQ12; KCNQ3; KCNQ5; KCNRG; KCNS1; KCNS3; KCNT1;KCNT2; KCNU1; KCNV1; KCNV2; KCTD10; KCTD11; KCTD12; KCTD13; KCTD15;KCTD16; KCTD1; KCTD21; KCTD2; KCTD3; KCTD6; KCTD7; KCTD9; KDELC1;KDELR1; KDM2A; KDM2B; KDM3A; KDM3B; KDM4B; KDM4C; KDM5A; KDM5B; KDM5C;KDM5D; KDM6A; KDM6B; KDR; KDSR; KEAP1; KEL; KERA; KHDC3L; KHDRBS2;KHDRBS3; KHK; KHSRP; KIAA0020; KIAA0040; KIAA0100; KIAA0101; KIAA0195;KIAA0226; KIAAO226L; KIAA0232; KIAA0319; KIAA0319L; KIAA0355; KIAA0391;KIAA0585; KIAA0825; KIAA0907; KIAA0922; KIAA1024; KIAA1033; KIAA1109;KIAA1147; KIAA1151; KIAA1211; KIAA1211L; KIAA1217; KIAA1279; KIAA1324;KIAA1324L; KIAA1377; KIAA1455; KIAA1462; KIAA1468; KIAA1524; KIAA1549;KIAA1551; KIAA159B; KIAA1715; KIAA1804; KIAA1841; KIAA1919; KIAA2022;KIDINS220; KIF11; KIF13A; KIF14; KIF15; KIF16B; KIF17; KIF18A; KIF1A;KIF1C; KIF20A; KIF20B; KIF21A; KIF21IB; KIF22; KIF23; KIF24; KIF25;KIF26A; KIF26B; KIF2A; KIF2B; KIF2C; KIF3A; KIF3B; KIF3C; KIF4A; KIF4B;KIF5A; KIF5B; KIF5C; KIF6; KIF7; KIF9; KIFAP3; KIFC1; KIFC3; KIN;KIR2DL1; KIR2DL2; KIR2DL3; KIR2DL4; KIR2DL5A; KIR2DL5B; KIR2DS1;KIR2DS2; KIR2DS3; KIR2DS4; KIR3DL1; KIR3DL2; KIR3DL3; KIRREL2; KIRREL3;KIRREL; KISS1; KISS1R; KIT; KITLG; KLB; KLC1; KLF10; KLF11; KLF12;KLF13; KLF14; KLF15; KLF16; KLF1; KLF2; KLF3; KLF4; KLF5; KLF6; KLF7;KLF8; KLF9; KLHDC1; KLHDC2; KLHDC8A; KLHDC8B; KLHL10; KLHL12; KLHL1;KLHL20; KLHL25; KLHL25; KLHL29; KLHL2; KLHL31; KLHL35; KLHL3; KLHL40;KLHL41; KLHL42; KLHL5; KLHL6; KLHL7; KLHL9; KL; KLK10; KLK11; KLK12;KLK13; KLK14; KLK15; KLK1; KLK2; KLK3; KLK4; KLK5; KLK6; KLK7; KLK8;KLK9; KLKB1; KLLN; KLRB1; KLRC1; KLRC2; KLRC4; KLRC4-KLKB1; KLRD1;KLRG1; KLRG2; KMO; KMT2A; KMT2B; KMT2C; KMT2D; KMT2E; KNG1; KNSTRN;KNTC1; KPNA1; KPNA2; KPNA3; KPNA4; KPNA6; KPNA7; KPNB1; KPRP; KPTN;KRAS; KRBDX4; KREMEN1; KRIT1; KRT10; KRT12; KRT13; KRT14; KRT15; KRT16;KRT17; KRT18; KRT19; KRT1; KRT20; KRT23; KRT2; KRT31; KRT32; KRT34;KRT35; KRT3; KRT4; KRT5; KRT6A; KRT6B; KRT6C; KRT71; KRT72; KRT74;KRT75; KRT76; KRT78; KRT7; KRT80; KRT81; KRT82; KRT83; KRT85; KRT86;KRT8; KRT9; KRTAP11-1; KRTAP5-1; KRTAP5-9; KSR1; KSR2; KTN1; KYNU;L1CAM; L2HGDH; L3MBTL1; L3MBTL2; L3MBTL3; L3MBTL4; LACC1; LACE1; LACRT;LACTB; LAD1; LAG3; LAIR1; LAIR2; LALBA; LAMA1; LAMA2; LAMA3; LAMA4;LAMA5; LAMB1; LAMB2; LAMB3; LAMB4; LAMC1; LAMC2; LAMC3; LAMP1; LAMP2;LAMP3; LAMTOR1; LAMTOR2; LAMTOR3; LANCL1; LANCL2; LAP3; LAPTM4B; LARGE;LARP1; LARP4; LARP6; LARP7; LARS2; LARS; LASIL; LASP1; LAT2; LAT; LATS1;LATS2; LAX1; LAYN; LBH; LBP; LBR; LBX1; LBX2; LCA5; LCAT; LCE1C; LCE3A;LCE3B; LCE3C; LCE3D; LCE3E; LCE5A; LCK; LCLAT1; LCMT1; LCN1; LCN2; LCOR;LCP1; LCP2; LCT; LDB1; LDB2; LDB3; LDHA; LDHAL6B; LDHB; LDHC; LDHD;LDLRAD3; LDLRAD4; LDLR; LDOC1; LDOC1L; LEAP2; LECT1; LECT2; LEF1;LEFTY1; LEFTY2; LEKR1; LEMD2; LEMD3; LED1; LEP; LEPROTL1; LETM1; LETMD1;LEUTX; LFNG; LGALS12; LGALS13; LGALS14; LGALS16; LGALS1; LGALS2;LGALS3BP; LGALS3; LGALS4; LGALS7B; LGALS8; LGALS9; LGALSL; LG11; LG12;LG14; LGMN; LGR4; LGR5; LGRD; LGSN; LHB; LHCGR; LHFP; LHFPL1; LHFPL2;LHFPL3; LHFPL4; LHFPL5; LHPP; LHX1; LHX2; LHX3; LHX4; LHX5; LHX6; LHX9;LIAS; LIF; LIFR; LIG1; LIG3; LIG4; LILRA1; LILRA2; LILRA3; LILRA4;LILRA5; LILRB1; LILRB2; LILRB3; LILRB4; LILRB5; LIM2; LIMA1; LIMCH1;LIMD1; LIMD2; LIMK1; LIMK2; LIMS1; LIMS2; LIN28B; LIN52; LIN7A; LIN7B;LIN7C; LIN9; LING01; LING02; LING04; LINS; LIPA; LIPC; LIPE; LIPF; LIPG;LIPH; LIPI; LIPN; LIPT1; LIPT2; LITAF; LIX1; LLGL1; LLGL2; LMAN1;LMAN1L; LMAN2L; LMBR1; LMBRD1; LMBRD2; LMCD1; LMF1; LMLN; LMNA; LMNB1;LMNB2; LMNTD1; LM01; LM02; LM03; LM07; LMDD1; LMDD3; LMTK2; LMTK3;LMX1A; LMX1B; LNPEP; LNX1; LNX2; LOC100288966; LOC101060321;LOC102723475; LOC102723996; LOC102724127; LOC102724560; LOC102724770;LOC102725016; LOC102725035; LOC400499; LOC400927-CSNK1 E; LOC645177;LONP1; LONRF1; LOR; LOXHD1; LOX; LOXL1; LOXL2; LOXL3; LOXL4; LPA; LPAR1;LPAR2; LPAR3; LPAR6; LPCAT1; LPCAT2; LPCAT3; LPCAT4; LPGAT1; LPIN1;LPIN2; LPL; LPD; LPP; LPPR2; LPPR4; LPXN; LRAT; LRBA; LRCH1; LRCH4;LRFN2; LRFN5; LRG1; LRGUK; LRIF1; LRIG1; LRIG3; LRIT1; LRIT3; LRMP;LRP10; LRP12; LRP18; LRP1; LRP2BP; LRP2; LRP4; LRP5; LRP6; LRPAP1;LRPPRC; LRR1; LRRC15; LRRC16A; LRRC16B; LRRC17; LRRC18; LRRC1; LRRC20;LRRC26; LRRC30; LRRC32; LRRC37A; LRRC37B; LRRC39; LRRC49; LRRC4B;LRRC4C; LRRC4; LRRC52; LRRC59; LRRC61; LRRC63; LRRC69; LRRC6; LRRC74A;LRRC7; LRRC8A; LRRC8C; LRRCC1; LRRFIP1; LRRFIP2; LRRK1; LRRK2; LRRN1;LRRN2; LRRN3; LRRN4; LRRTM1; LRRTM2; LRRTM3; LRRTM4; LRSAM1; LRTM1;LRTOMT; LSAMP; LSM11; LSM1; LSM2; LSM3; LSM4; LSM5; LSM6; LSM7; LSP1;LSR; LSS; LST1; LTA4H; LTA; LTB4R2; LTB4R; LTB; LTBP1; LTBP2; LTBP3;LTBP4; LTBR; LTC4S; LTF; LTK; LUC7L3; LUC7L; LUM; LURAP1L; LUZP4; LUZP6;LVRN; LXN; LY6D; LY6E; LY6G5B; LY6G5C; LY6G6C; LY6G6F; LY6K; LY75-CD302;LY75; LY86; LY96; LY9; LYL1; LYN; LYNX1; LYPD1; LYPD2; LYPD3; LYPD4;LYPD5; LYPD6; LYPD8; LYPLA1; LYPLAL1; LYRM1; LYRM4; LYRM7; LYRM9; LYST;LYVE1; LYZ; LYZL1; LYZL2; LYZL6; LZTFL1; LZTR1; LZTS1; M6PR; MAATS1;MAB2IL1; MAB21L2; MAB21L3; MACC1; MACROD1; MACROD2; MAD1L1; MAD2L1BP;MAD2L1; MAD2L2; MADCAM1; MADD; MAEA; MAEL; MAF1; MAFA; MAFB; MAFF; MAFG;MAF; MAFK; MAGEA10; MAGEA11; MAGEA12; MAGEA1; MAGEA2B; MAGEA3; MAGEA4;MAGEA6; MAGEA9; MAGEB17; MAGEB1; MAGEB2; MAGEB6; MAGEC1; MAGEC2; MAGEC3;MAGED1; MAGED2; MAGED4B; MAGED4; MAGEE1; MAGEH1; MAGEL2; MAG; MAGI1;MAGI2; MAGI3; MAGT1; MAK16; MAK; MAL; MALL; MALRD1; MAML1; MAML2; MAML3;MAMLD1; MAN1A1; MAN1B1; MAN2A1; MAN2A2; MAN2B1; MAN2C1; MANBA; MANEA;MANF; MANSC1; MAOA; MAOB; MAP10; MAP1A; MAP1B; MAP1LC3A; MAP1LC3B2;MAP1LC3B; MAP1S; MAP2; MAP2K1; MAP2K2; MAP2K3; MAP2K4; MAP2K5; MAP2K6;MAP2K7; MAP3K10; MAP3K11; MAP3K12; MAP3K13; MAP3K14; MAP3K19; MAP3K1;MAP3K2; MAP3K3; MAP3K4; MAP3K5; MAP3K6; MAP3K7CL; MAP3K7; MAP3K8;MAP3K9; MAP4; MAP4K1; MAP4K2; MAP4K3; MAP4K4; MAP4K5; MAP6; MAP7; MAP9;MAPK10; MAPK11; MAPK12; MAPK13; MAPK14; MAPK15; MAPK1; MAPK3; MAPK6;MAPK7; MAPK8; MAPK8IP1; MAPK8IP2; MAPK8IP3; MAPK9; MAPKAP1; MAPKAPK2;MAPKAPK3; MAPKBP1; MAPRE1; MAPRE2; MAPRE3; MAPT; MARC1; MARC2; MARCH1;MARCH2; MARCH5; MARCH6; MARCH7; MARCH8; MARCKS; MARC0; MARK1; MARK2;MARK3; MARK4; MARS2; MARS; MARVELD1; MARVELD2; MARVELD3; MAS1; MAS1L;MASP1; MAST2; MAST4; MASTL; MAT1A; MAT2A; MAT2B; MATK; MATN2; MATN3;MATR3; MAU2; MAVS; MAX; MAZ; MB21D1; MB21D2; MBD1; MBD2; MBD3; MBD3L2;MBD4; MBD5; MBD6; MB; MBIP; MBL2; MBNL1; MBNL2; MBDAT1; MBDAT2; MBDAT4;MBP; MBTD1; MBTPS1; MBTPS2; MC1R; MC2R; MC3R; MC4R; MC5R; MCAM; MCAT;MCCC1; MCCC2; MCCD1; MCC; MCEE; MCF2; MCF2L2; MCF2L; MMCFD2; MCHR1;MCHR2; MCIDAS; MCM10; MCM2; MCM3AP; MCM3; MCM4; MCM5; MCM6; MCM7; MCM8;MCM9; MCMBP; MCOLN1; MCOLN3; MCPH1; MCRS1; MCTP1; MCTP2; MCTS1; MCU;MCUR1; MDC1; MDFIC; MDFI; MDGA1; MDGA2; MDH1; MDH2; MDK; MDM1; MDM2;MDM4; ME1; ME2; ME3; MEA1; MECOM; MECP2; MED12; MED12L; MED13; MED13L;MED14; MED15; MED16; MED17; MED19; MED1; MED22; MED23; MED24; MED25;MED28; MED29; MED30; MED4; MED6; MED9; MEF2A; MEF2B; MEF2BNB-MEF2B;MEF2C; MEF2D; MEFV; MEGF10; MEGF11; MEGFB; MEGF9; MEI1; MEIS1; MEIS2;MELK; MEM01; MEN1; MEOX1; MEOX2; MEP1A; MEPE; MERTK; MESDC1; MESDC2;MESP2; MEST; METAP1D; METAP1; METAP2; MET; METRN; METTL13; METTL16;METTL17; METTL18; METTL1; METTL21A; METTL21B; METTL21C; METTL24; METTL6;METTL7A; METTL9; MEX3B; MEX3C; MEX3D; MFAP3; MFAP4; MFAP5; MFGE8;MFHAS1; MFI2; MFN1; MFRP; MFSD11; MFSD12; MFSD1; MFSD6; MFSD7; MFSD8;MGA; MGAM; MGARP; MGAT1; MGAT2; MGAT3; MGAT4A; MGAT4B; MGAT4C; MGAT5B;MGAT5; MGEA5; MGLL; MGME1; MGMT; MGP; MGRN1; MGST1; MGST2; MGST3; MIA2;MIA3; MIA; MIB1; MIB2; MICA; MICAL2; MICALCL; MICB; MICU1; MICU3; MID1;MID2; MIEN1; MIER2; MIER3; MIF; MILR1; MINA; MINK1; MINPP1; MIOX; MIPEP;MIP; MIPUL1; MIR1-1HG; MIS18BP1; MITF; MIXL1; MKI67; MKKS; MKL1; MKL2;MKLN1; MKNK1; MKNK2; MKRN1; MKRN3; MKS1; MLANA; MLC1; MLEC; MLF1; MLF2;MLH1; MLH3; MLKL; MLLT10; MMLT1; MLLT3; MLLT4; MLLT6; MLN; MLNR; MLPH;MLST8; MLX; MLXIP; MLXIPL; MLYCD; MMAA; MMAB; MMADHC; MMD2; MMD; MME;MMEL1; MMP10; MMP11; MMP12; MMP13; MMP14; MMP15; MMP16; MMP17; MMP19;MMP1; MMP20; MMP21; MMP24; MMP25; MMP26; MMP28; MMP2; MMP3; MMP7; MMP8;MMP9; MMRN1; MMRN2; MMS19; MMS22L; MN1; MNAT1; MNDA; MNS1; MNT; MNX1;MOAP1; MOB1A; MOB1B; MOB2; MOB3B; MOB4; MOBP; MOCOS; MOCS1; MOCS2;MOGAT1; MOGAT2; MOGAT3; MOG; MOGS; MDK; MDN1A; MDN1B; MDN2; MORC3;MORF4L1; MDRN1; MDRN2; MDRN5; MOS; MOV10L1; MPC1; MPC2; MPDU1; MPDZ;MPEG1; MPG; MPHOSPH10; MPHOSPH6; MPHDSPH8; MPHOSPH9; MPI; MPLKIP; MPO;MPP1; MPP2; MPP3; MPP5; MPP7; MPPE1; MPPED2; MPRIP; MPST; MPV17;MPV17L2; MPZ; MPZL1; MPZL2; MPZL3; MR1; MRAP2; MRAP; MRAS; MRC1; MRC2;MRE11A; MREG; MRFAP1; MRGBP; MRGPRF; MRGPRX1; MRGPRX3; MRGPRX4; MRI1;MRM1; MROH2B; MR0; MRPL10; MRPL11; MRPL13; MRPL15; MRPL17; MRPL19;MRPL1; MRPL23; MRPL28; MRPL33; MRPL36; MRPL3; MRPL40; MRPL41; MRPL44;MRPL49; MRPL52; MRPL9; MRPS11; MRPS12; MRPS16; MRPS18B; MRPS22; MRPS23;MRPS28; MRPS30; MRPS31; MRPS33; MRPS6; MRPS7; MRPS9; MRRF; MRS2; MRVI1;MS4AI2; MS4A1; MS4A2; MS4A3; MS4A4A; MS4A6A; MS4A8; MSANTD3-TMEFF1; MSC;MSGN1; MSH2; MSH3; MSH6; MSI1; MSI2; MSLN; MSMB; MSMO1; MSMP; MSN; MSR1;MSRA; MSRB2; MSRB3; MST1; MST1R; MSTN; MSTO1; MSX1; MSX2; MT1A; MT1B;MT1E; MT1F; MT1G; MT1H; MT1M; MT1X; MT2A; MT3; MT4; MTA1; MTA2; MTA3;MTAP; MTBP; MTCH1; MTCH2; MTCL1; MTCP1; MTDH; MTERF1; MTF1; MTFMT;MTFP1; MTG1; MTHFD1; MTHFD1L; MTHFD2; MTHFR; MTHFS; MTIF2; MTIF3; MTL5;MTM1; MTMR11; MTMR12; MTMR14; MTMR1; MTMR2; MTMR3; MTMR4; MTMR6; MTMR7;MTMR8; MTMR9; MTNR1A; MTNR1B; MT01; MTPAP; MTPN; MTRF1; MTR; MTRNR2L7;MTRR; MTSS1; MTTP; MTURN; MTUS1; MTUS2; MTX1; MTX2; MUC12; MUC13; MUC15;MUC17; MUC19; MUC1; MUC20; MUC21; MUC22; MUC2; MUC3A; MUC4; MUC5AC;MUC5B; MUC6; MUC7; MUCL1; MUM1; MURC; MUS81; MUSK; MUT; MUTYH; MVB12B;MVD; MVK; MVP; MX1; MX2; MXD1; MXD3; MXD4; MXI1; MXRA5; MYADM; MYBBP1A;MYB; MYBL1; MYBL2; MYBPC1; MYBPC2; MYBPC3; MYBPH; MYCBP2; MYCBPAP; MYC;MYON; MYCT1; MYD88; MYDGF; MYEF2; MYE0V; MYF5; MYF6; MYH10; MYH11;MYH13; MYH14; MYH15; MYH; MYH2; MYH3; MYH4; MYH6; MYH7B; MYH7; MYH8;MYH9; MYL12A; MYL12B; MYL1; MYL2; MYL3; MYL4; MYL6; MYL7; MYL9; MYLIP;MYLK2; MYLK3; MYLK; MYLPF; MYNN; MO10; MYO15A; MYO16; MYO18B; MYO1A;MYO1B; MYO1C; MYO1D; MYO1E; MYO1F; MYO3A; MYO3B; MYO5A; MYO5B; MYO5C;MYO6; MYO7A; MYO7B; MYO9A; MYO9B; MYOCD; MYOC; MYOD1; MYOF; MYOG; MYOM1;MYOM2; MYOT; MYOZ1; MYOZ2; MYOZ3; MYPN; MYRF; MYRFL; MYRIP; MYT1; MYT1L;MYZAP; MZB1; MZF1; N4BP1; N4BP2L1; N4BP2L2; NAA10; NAA15; NAA16; NAA20;NAA25; NAA30; NAA35; NAA40; NAA50; NAA60; NAAA; NAALAD2; NAALADL1;NAALADL2; NAB1; NAB2; NABP1; NABP2; NACA; NACC1; NACC2; NADSYN1; NAE1;NAF1; NAGA; NAGK; NAGLU; NAGPA; NAGS; NAIP; NALCN; NAMPT; NANOG; NANOS1;NANOS2; NANOS3; NANS; NAP1L1; NAP1L3; NAP1L4; NAP1L5; NAPA; NAPEPLD;NAPG; NAPRT; NAPSA; NARFL; NARR; MARS; NAT10; NAT14; NAT1; NAT2; NAT6;NAT8B; NAT8; NAT8L; NAV1; NAV2; NAV3; NBAS; NBEA; NBEAL1; NBEAL2; NBN;NBPF3; NBR1; NCALD; NCAM1; NCAM2; NCAN; NCAPD2; NCAPD3; NCAPG2; NCAPG;NCBP2; NCEH1; NCF1; NCF2; NCF4; NCK1; NCK2; NCKAP1; NCKAP1L; NCKAP5;NCKIPSD; NCL; NCOA1; NCOA2; NCOA3; NCOA4; NCOA5; NCOA6; NCOA7; NCOR1;NCOR2; NCR1; NCR2; NCR3; NCR3LG1; NCS1; NCSTN; NDC80; NDE1; NDEL1;NDFIP1; NDFIP2; NDNF; NDN; NDP; NORG1; NORG2; NORG3; NORG4; NDST1;NDST2; NDST3; NDST4; NDUFA10; NDUFA11; NDUFA12; NDUFA13; NDUFA1; NDUFA2;NDUFA5; NDUFA6; NDUFA9; NDUFAB1; NDUFAF1; NDUFAF2; NDUFAF3; NDUFAF4;NDUFAF5; NDUFAF6; NDUFB10; NDUFB11; NDUFB2; NDUFB3; NDUFB4; NDUFB5;NDUFB6; NDUFB8; NDUFB9; NDUFC2; NDUFS1; NDUFS2; NDUFS3; NDUFS4; NDUFS6;NDUFS7; NDUFS8; NDUFV1; NDUFV2; NDUFV3; NEB; NEBL; NECAB1; NECAB3;NECAP1; NEDD1; NEDD4; NEDD4L; NEDD8; NEDD9; NEFH; NEFM; NEIL1; NEIL2;NEIL3; NEK10; NEK11; NEK1; NEK2; NEK3; NEK4; NEK6; NEK7; NEK8; NEK9;NELFA; NELFB; NELFCD; NELFE; NELL1; NELL2; NEMF; NE01; NES; NET1; NET01;NET02; NEU1; NEU3; NEURL1; NEURL2; NEUROD1; NEUROD2; NEUROD4; NEUROD6;NEUROG1; NEUROG2; NEUROG3; NF1; NF2; NFAM1; NFASC; NFAT5; NFATC1;NFATC2; NFATC3; NFATC4; NFE2; NFE2L1; NFE2L2; NFE2L3; NFIA; NFIB; NFIC;NFIL3; NFIX; NFKB1; NFKB2; NFKBIA; NFKBIB; NFKBIE; NFKBIL1; NFKBIZ;NFRKB; NFS1; NFU1; NFYA; NFYB; NFYC; NGB; NGDN; NGEF; NGF; NGFRAP1;NGFR; NGLY1; NHEJ1; NHLH1; NHLRC1; NHLRC3; NHP2; NHP2L1; NHS; NHSL1;NICN1; NID1; NID2; NIF3L1; NIM1K; NIN; NINJ1; NINJ2; NINL; NIPA1; NIPA2;NIPAL3; NIPAL4; NIPBL; NIPSNAP1; NIPSNAP3B; NISCH; NIT1; NIT2; NKAIN2;NKAIN3; NKAP; NKD1; NKD2; NKG7; NKIRAS1; NKIRAS2; NKRF; NKTR; NKX1-1;NKX1-2; NKX2-1; NKX2-2; NKX2-3; NKX2-5; NKX2-5; NKX2-6; NKX3-1; NKX6-1;NKX6-2; NLE1; NLGN1; NLGN2; NLGN3; NLGN4X; NLGN4Y; NLK; NLN; NLRC3;NLRC4; NLRC5; NLRP10; NLRP11; NLRP12; NLRP13; NLRP14; NLRP1; NLRP2;NLRP3; NLRP4; NLRP5; NLRP6; NLRP7; NLRP8; NLRP9; NMB; NMBR; NME1;NME1-NME2; NME2; NME3; NME4; NME5; NME6; NME7; NME8; NME9; NMI; NMNAT1;NMNAT2; NMNAT3; NMS; NMT1; NMT2; NMU; NMUR1; NMUR2; NNAT; NNMT; NNT;NDA1; NDB1; NDBDX; NOC3L; NOD1; NOD2; NODAL; NOG; NOL11; NOL3; NOL4;NOL6; NOL8; NOLC1; NOM1; NOMO1; NONO; NOP10; NOP14; NOP16; NOP2; NOP56;NOP9; NOS1AP; NOS1; NOS2; NOS3; NOSIP; NOSTRIN; NOTCH1; NOTCH2; NOTCH3;NOTCH4; NOTUM; NOVA1; NOVA2; NOV; NOX1; NOX3; NOX4; NOX5; NOXA1; NOXO1;NPAP1; NPAS2; NPAS3; NPAS4; NPAT; NPB; NPBWR1; NPC1; NPC1L1; NPC2;NPDC1; NPEPL1; NPEPPS; NPFF; NPFFR2; NPHP1; NPHP3; NPHP4; NPHS1; NPHS2;NPL; NPLOC4; NPM1; NPM2; NPNT; NPPC; NPR1; NPR2; NPR3; NPRL2; NPRL3;NPS; NPSR1; NPTN; NPTX1; NPTX2; NPTXR; NPVF; NPW; NPY1R; NPY2R; NPY5R;NPY; NQ01; NQ02; NROB1; NR1D1; NR1D2; NR1H2; NR1H3; NR1H4; NR1I2; NR1I3;NR2C1; NR2C2; NR2E1; NR2E3; NR2F1; NR2F2; NR2F6; NR3C1; NR3C2; NR4A1;NR4A2; NR4A3; NR5A1; NR5A2; NR6A1; NRAP; NRARP; NRBP1; NRBP2; NRCAM;NRD1; NRDE2; NREP; NRF1; NRG1; NRG2; NRG3; NRG4; NRGN; NRIP1; NRIP2;NRK; NRL; NRM; NRN1; NRP1; NRP2; NRSN1; NRSN2; NRTN; NRXN1; NRXN2;NRXN3; NSA2; NSD1; NSDHL; NSF; NSFL1C; NSG1; NSMAF; NSMCE2; NSMF; NSRP1;NSUN2; NSUN3; NSUN5; NSUN7; NT5C1B; NT5C1B-RDH14; NT5C2; NT5C3A; NT5C;NT5DC1; NT5DC3; NT5E; NT5M; NTAN1; NTF3; NTF4; NTHL1; NTM; NTN1; NTN4;NTNG1; NTNG2; NTPCR; NTRK1 ; NTRK2; NTRK3; NTS; NTSR1; NTSR2; NUAK1;NUAK2; NUB1; NUBP1; NUBP2; NUBPL; NUCB1; NUCB2; NUCKS1; NUDCD1; NUDCD3;NUDC; NUDT10; NUDT11; NUDT15; NUDT19; NUDT1; NUDT21; NUDT2; NUDT3;NUDT6; NUDT7; NUF2; NUFIP1; NUFIP2; NUGGC; NUMA1; NUMB; NUMBL; NUP153;NUP155; NUP205; NUP210; NUP214; NUP35; NUP37; NUP43; NUP50; NUP62;NUP85; NUP88; NUP93; NUP98; NUPL2; NUPR1; NUS1; NUSAP1; NUTF2; NUTM1;NUTM2A; NUTM2B; NVL; NWD1; NXF1; NXF2B; NXF3; NXF5; NXN; NXNL1; NXNL2;NXPE1; NXPE2; NXPE4; NXPH1; NXPH2; NXT1; NXT2; NYAP2; NYX; OARD1; OAS1;OAS2; OAS3; OASL; OAT; OAZ1; OAZ2; OBFC1; OBP2A; OBSCN; OBSL1; OC90;OCA2; OCIAD1; OCIAD2; OCLM; OCLN; OCM2; OCM; OCRL; ODAM; ODC1; ODF1;ODF3B; ODF4; OFCC1; OFD1; OGDH; OGDFIL; IGFOD1; OGFR; OGG1; OGN; OGT;OIP5; OIT3; OLA1; OLFM1; OLFM2; OLFM4; OLFML2B; OLIG1; OLIG2; OLIG3;OLR1; OMG; OMP; ONECUT1; ONECUT2; OPA1; OPA3; OPCML; OPHN1; OPN1LW;OPN1MW2; OPN1SW; OPN3; OPN4; OPN5; OPRK1; OPRL1; OPRM1; OPTC; OPTN;OR10A2; OR10A4; OR10C1; OR10J1; OR10J3; OR10J5; OR10K1; OR10K2; OR10R2;OR10X1; OR10Z1; OR11A1; OR12D2; OR12D3; OR13C3; OR13C4; OR13F1; OR13G1;OR13J1; OR14J1; OR1A1; OR1C1; OR1D2; OR1E1; OR1E2; OR1J2; OR1K1; OR1L8;OR1 M1; OR1N1; OR1N2; OR2A25; OR2AG1; OR2AK2; OR2AT4; OR2B2; OR2B3;OR2B6; OR2C1; OR2F2; OR2G2; OR2G3; OR2H2; OR2J2; OR2J3; OR2L2; OR2M3;OR2M4; OR2M7; OR2S2; OR2T10; OR2T12; OR2T1; OR2T2; OR2T33; OR2T4; OR2T5;OR2W1; OR2Y1; OR2Z1; OR3A1; OR4A15; OR4C12; OR4C13; OR4C6; OR4D10;OR4K13; OR4P4; OR4S2; OR51A2; OR51A7; OR51E1; OR51E2; OR51F2; OR51V1;OR52B2; OR52B4; OR52D1; OR52E6; OR52I1; OR52I2; OR52K1; OR52K2; OR52M1;OR5D18; OR5H2; OR5H6; OR5K1; OR5K2; OR5V1; OR6B1; OR6B2; OR6C1; OR6F1;OR6K2; OR6K3; OR6K6; OR6N1; OR6N2; OR6X1; OR6Y1; OR7C1; OR7D2; OR7E24;OR8S1; OR9K2, OR9Q2; ORAI1; ORAI3; ORAOV1; ORC2; ORC3; ORC4; ORC5; ORC6;ORM1; ORM2; ORMDL3; OS9; OSBP2; OSBP; OSBPL10; OSBPL11; OSBPL1A; OSBPL2;OSBPL3; OSBPL5; OSBPL6; OSBPL8; OSBPL9; OSCAR; OSER1; OSGEP; OSGIN1;OSM; OSMR; OSR1; OSR2; OSTF1; OSTM1; OTC; OTOA; OTOF; OTOG; OTOGL;OTOL1; OTOP1; OTOR; OTP; OTUB1; OTUD1; OTUD4; OTUD7A; OTUD7B; OTULIN;OTX1; OTX2; OVCA2; OVOL1; OVOL2; OXA1L; OXCT1; OXER1; OXGR1; OXR1;OXSR1; OXT; OXTR; P2RX1; P2RX2; P2RX3; P2RX4; P2RX5; P2RX6; P2RX7;P2RY11; P2RY12; P2RY13; P2RY14; P2RY1; P2RY2; P2RY4; P2RY6; P2RY8; P3H2;P3H3; P3H4; P4HA1; P4HA2; P4HB; P4HTM; PA2G4; PABPC1; PABPC3; PABPC4L;PABPN1; PACRG; PACS1; PACS2; PACSIN1; PACSIN2; PADI4; PAEP; PAF1;PAFAH1B1; PAFAH1B2; PAFAH2; PAG1; PAGE1; PAGE4; PAGE5; PAGR1; PAH;PAICS; PAIP1; PAIP2; PAK1; PAK1IP1; PAK2; PAK3; PAK4; PAK6; PAK7; PALB2;PALD1; PALLD; PALM2-AKAP2; PAM16; PAM; PAMR1; PAN2; PAN3; PANK1; PANK2;PANX1; PANX2; PAPD7; PAPL; PAP0LA; PAP0LG; PAPPA2; PAPPA; PAPSS1;PAPSS2; PAQR3; PAQR5; PAQR7; PARD3B; PARD3; PARD6A; PARD6B; PARG; PARK2;PARL; PARM1; PARM1; PARP12; PARP14; PARP15; PARP1; PARP2; PARP3; PARP4;PARP6; PARP9; PARPBP; PARS2; PARVA; PARVB; PARVG; PASD1; PASK; PATE1;PATZ1; PAWR; PAX1; PAX2; PAX3; PAX4; PAX5; PAX6; PAX8; PAX9; PAXIP1;PBK; PBLD; PBOV1; PBRM1; PBX1; PBX2; PBX3; PBX4; PCBD1; PCBD2; PCBP1;PCBP2; PCBP3; PCBP4; PCCA; PCCB; PCDH10; PCDH11X; PCDH11Y; PCDH15;PCDH17; PCDH18; PCDH19; PCDH1; PCDH20; PCDH7; PCDH8; PCDH9; PCDHA1;PCDHA4; PCDHA6; PCDHB1; PCDHB2; PCDHB3; PCDHB8; PCDHGA11; PCDHGA3;PCDHGB4; PCDHGB6; PCDHGC3; PCED1B; PCF11; PCGF1; PCGF2; PCGF3; PCGF5;PC; PCID2; PCK1; PCK2; PCL0; PCM1; PCMT1; PCMTD1; PCNA; PCNT; PCNXL2;PCNXL4; PCOLCE2; PCOLCE; PCP2; PCP4; PCSK1; PCSK1N; PCSK2; PCSK4; PCSK5;PCSK6; PCSK7; PCTP; PCYT1A; PCYT1B; PDAP1; PDCD1O; PDCD1; PDC1LG2;PDCD2; PDCD4; PDCD5; PDCD6; PDCD6IP; PDCD7; PDC; PDCL2; PDCL3; PDE10A;PDE11A; PDE12; PDE1A; PDE1B; PDE1C; PDE2A; PDE3A; PDE3B; PDE4A; PDE4D;PDE5A; PDE6A; PDE6B; PDE6C; PDE6D; PDE7A; PDE7BP; PDE8A; PDE8B; PDE9A;PDF; PDGFA; PDGFB; PDGFC; PDGFD; PDGFRA; PDGFRB; PDGFRL; PDHA1; PDHB;PDHX; PDIA2; PDIA3; PDIA4; PDIA5; PDIA6; PDK1; PDK2; PDK3; PDK4; PDLIM1;PDLIM2; PDLIM3; PDLIM4; PDLIM5; PDLIM7; PDP1; PDP2; PDPK1; PDPR; PDRG1;PDS5A; POS5B; PDSS1; PDSS2; PDX1; PDHC1; PDXK; PDXP; PDYN; PDZD2; PDZD4;PDZD7; PDZD8; PDZD8; PDZK1; PDZRN3; PDZRN4; PEA15; PEAK1; PEAR1; PEBP1;PEBP4; PECAM1; PECR; PEG10; PEG3; PELI1; PELI2; PELP1; PEMT; PENK; PEPD;PER1; PER2; PER3; PERM1; PERP; PES1; PET100; PET117; PEX11A; PEX12;PEX13; PEX14; PEX15; PEX19; PEX1; PEX26; PEX2; PEX3; PEX5; PEX5L; PEX6;PEX7; PF4; PF4V1; PFDN4; PFDN5; PFDN6; PFKFB1; PFKFB2; PFKFB3; PFKFB4;PFKL; PFKM; PFKP; PFN1; PFN2; PGA3; PGA4; PGA5; PGAM1; PGAM2; PGAM4;PGAP1; PGAP2; PGAP3; PGBD1; PGBD5; PGC; PGD; PGF; PGGT1B; PGK1; PGK2;PGLS; PGLYRP1; PGLYRP2; PGLYRP3; PGLYRP4; PGM3; PGPEP1; PGP; PGR;PGRMC1; PGRMC2; PHACTR1; PHACTR2; PHACTR3; PHB2; PHB; PHC1; PHC2; PHC3;PHEX; PHF10; PHF11; PHF12; PHF19; PHF1; PHF20; PHF21A; PHF23; PHF2;PHF3; PHF5A; PHF5; PHF6; PHF8; PHGHD; PHIP; PHKA1; PHKA2; PHKB; PHKG1;PHKG2; PHLDA1; PHLDA2; PHLDA3; PHLDB1; PHLPP1; PHLPP2; PHDX2A; PHDX2B;PHPT1; PHRF1; PHTF1; PHTF2; PHYH; PHYHIP; PHYKPL; PI15; PI16; PI3;PI4K2A; PI4K2B; PI4KA; P14KB; PIAS1; PIAS2; PIAS4; PIBF1; PICALM; PICK1;PID1; PIDD1; PIEZ01; PIEZ02; PIF1; PIF0; PIGA; PIGF; PIGG; PIGL; PIGM;PIGN; PIGO; PIGP; PIGQ; PIGR; PIGT; PIGU; PIGW; PIGY; PIH1D1; PIK3AP1;PIK3C2A; PIK3C2B; PIK3C2G; PIK3C3; PIK3CA; PIK3CB; PIK3CD; PIK3CG;PIK3IP1; PIK3R1; PIK3R2; PIK3R3; PIK3R4; PIK3R5; PIKFYVE; PILRA; PIM1;PIM2; PIM3; PIN1; PIN4; PINX1; PIP4K2A; PIP4K2B; PIP4K2C; PIPSK1A;PIPSK1B; PIP5K1C; PIP5KL1; PIP; PIPOX; PIR; PISD; PITPNA; PITPNM1;PITPNM3; PITRM1; PITX1; PITX2; PITX3; PIWIL1; PIWIL2; PIWIL3; PIWIL4;PJA1; PJA2; PKD1; PKD1L1; PKD1L2; PKD1L3; PKD2; PKD2L1; PKDCC; PDREJ;PKHD1; PKIA; PKIB; PKLR; PKM; PKMYT1; PKN1; PKN2; PKN3; PKNDX1; PKNDX2;PKP1; PKP2; PKP3; PKP4; PLA1A; PLA2G10; PLA2G12A; PLA2G12B; PLA2G15;PLA2G16; PLA2G18; PLA2G3; PLA2G4A; PLA2G4B; PLA2G4C; PLA2G4D; PLA2G5;PLA2G6; PLA2G7; PLA2R1; PLAA; PLAC1; PLAC8; PLAG1; PLAGL1; PLAGL2; PLAT;PLAU; PLAUR; PLB1; PLBD1; PLCB1; PLCB2; PLCB3; PLCB4; PLCD1; PLCD3;PLCD4; PLCE1; PLCG1; PLCG2; PLCH1; PLCL1; PLCL2; PLCXD2; PLCXD3; PLCZ1;PLD1; PLD2; PLD3; PLD4; PLD5; PLEC; PLEK2; PLEKHA1; PLEKHA2; PLEKHA5;PLEKHA6; PLEKHA7; PLEKHB1; PLEKHD1; PLEKHF1; PLEKHF2; PLEKHG1; PLEKHG2;PLEKHG3; PLEKHG4; PLEKHG6; PLEKHH2; PLEKHM1; PLEKHO1; PLEKHO2; PLEK;PLG; PLGLB2; PLIN1; PLIN2; PLIN3; PLIN4; PLIN5; PLK1; PLK2; PLK4; PLK5;PLLP; PLN; PLOD2; PLP1; PLP2; PLRG1; PLS1; PLS3; PLSCR1; PLSCR3; PLSCR4;PLSCR5; PLTP; PLVAP; PLXDC1; PLXDC2; PLXNA1; PLXNA2; PLXNA3; PLXNA4;PLXNB1; PLXNB3; PLXNC1; PLXND1; PM2OD1; PMAIP1; PMCH; PMEL; PMEPA1;PMF1-BGLAP; PMF1; PML; PMM1; PMM2; PMP22; PMPCA; PMPCB; PMS1; PMS2;PMVK; PNCK; PNKD; PNKP; PNLDC1; PNLIP; PNLIPRP2; PNMA1; PNMA2; PNMT;PNN; PND1; PNOC; PNP; PNPLA1; PNPLA2; PNPLA3; PNPLA4; PNPLA5; PNPLA6;PNPLA8; PNPO; PNPT1; PNRC1; POC1A; POC1B; POC5; PODXL; PDF1B; PDFUT1;PDFUT2; POGK; POGLUT1; POLA1; POLA2; POLD1; POLD2; POLD3; POLD4;POLDIP3; POLE2; POLE3; POLE4; POLE; POLG2; POLG; POLH; POLI; POLK; POLL;POLM; POLN; POLQ; POLR1A; POLR1B; POLR1C; POLR1D; PDLR2A; PDLR2B;POLR2C; POLR2D; POLR2E; POLR2F; POLR2G; POLR2H; POLR2J; POLR2K; POLR2M;POLR3A; POLR3B; POLR3E; POLR3K; POLRMT; POM121; POMC; POMGNT1; POMGNT2;POMK; POMP; POMT1; POMT2; POMZP3; PON1; PON2; PON3; POP1; POP4; POPDC3;PORCN; POR; POSTN; POT1l; POTED; POTEF; POTEG; POTEH; POTEM; POU1F1;POU2AF1; POU2F1; POU2F2; POU2F3; POU3F2; POU3F3; POU3F4; POU4F1; POU4F2;POU4F3; POU5F1B; POU5F1; POU6F1; POU6F2; PPA1; PPA2; PPAP2A; PPAP2C;PPAPDC1B; PPAPDC2; PPAPDC3; PPARA; PPARD; PPARGC1A; PPARGC1B; PPARG;PPAT; PPBP; PPCDC; PPEF1; PPEF2; PPFIA1; PPFIA2; PPFIA4; PPFIBP1;PPFIBP2; PPIA; PPIB; PPIC; PPID; PPIF; PPIG; PPIL1; PPIL2; PPIL3;PPIP5K1; PPL; PPM1A; PPM1B; PPM1D; PPM1E; PPM1F; PPM1G; PPM1H; PPM1K;PPM1L; PPM1M; PPME1; PPOX; PPP1CA; PPP1CC; PPP1R10; PPP1R11; PPP1R12A;PPP1R12B; PPP1R12C; PPP1R13B; PPP1R13L; PPP1R14A; PPP1R14B; PPP1R14C;PPP1R15A; PPP1R15B; PPP1R17; PPP1R18; PPP1R1A; PPP1R1B; PPP1R2; PPP1R3A;PPP1R3B; PPP1R3C; PPP1R42; PPP1R7; PPP1R9A; PPP2CA; PPP2CB; PPP2R1A;PPP2R1B; PPP2R2A; PPP2R2B; PPP2R2C; PPP2R3A; PPP2R3B; PPP2R4; PPP2R5A;PPP2R5B; PPP2R5C; PPP2R5D; PPP2R5E; PPP3CA; PPP3CB; PPP3CC; PPP3R1;PPP3R2; PPP4C; PPP4R1; PPP5C; PPP6C; PPP6R2; PPP6R3; PPRC1; PPT2; PPY;PQBP1; PQLC3; PRAC1; PRAC2; PRADC1; PRAF2; PRAM1; PRAME; PRAP1; PRB1;PRB2; PRB3; PRB4; PRC1; PRCC; PRCD; PRCP; PRDM10; PRDM11; PRDM13;PRDM14; PRDM1; PRDM4; PRDM5; PRDM6; PRDM7; PRDM8; PRDM9; PRDX2; PRDX3;PRDX4; PRDX5; PRDX6; PREB; PRELP; PREP; PREPL; PREX1; PREX2; PRF1; PRG2;PRG4; PRH1; PRH2; PRICKLE1; PRICKLE2; PRICKLE4; PRIM1; PRIMA1; PRIMPOL;PRKAA1; PRKAB1; PRKACA; PRLACB; PRKACG; PRKAG1; PRKAG2; PRKAG3; PRKAR1A;PRKAR1B; PRKAR2A; PRKAR2B; PRKCA; PRKCB; PRKCDBP; PRKCD; PRKCE; PRKCG;PRKCH; PRKCI; PRKCQ; PRKCSH; PRKCZ; PRKD1; PRKD3; PRKDC; PRKG1; PRKG2;PRKRA; PRKRIR; PRKX; PRLH; PRL; PRLHR; PRLR; PRM1; PRM2; PRM3; PRMT1;PRMT2; PRMT3; PRMT5; PRMT8; PRND; PRNP; PROC; PROCR; PRODH; PROK2;PROKR1; PROKR2; PROL1; PROM1; PROM2; PROP1; PROS1; PROSER1; PROX1; PROZ;PRPF19; PRPF31; PRPF38B; PRPF3; PRPF40A; PRPF4B; PRPF4; PRPF6; PRPF8;PRPH2; PRPH; PRPS1; PRPS1L1; PRPS2; PRPSAP1; PRPSAP2; PRR11; PRR13;PRR15; PRR16; PRR34; PRR3; PRR5; PRR9; PRRC1; PRRC2A; PRRC2C; PRRG4;PRRT1; PRRT2; PRRX1; PRRX2; PRSS12; PRSS16; PRSS1; PRSS21; PRSS22;PRSS23; PRSS27; PRSS2; PRSS33; PRSS35; PRSS3; PRSS50; PRSS53; PRSS55;PRSS57; PRSS58; PRSS8; PRTFDC1; PRTG; PRTN3; PRUNE2; PRUNE; PRX; PRY;PSAP; PSAT1; PSCA; PSD3; PSD4; PSD; PSEN1; PSEN2; PSENEN; PSG1; PSG2;PSG5; PSG6; PSG8; PSG9; PSIP1; PSKH1; PSMA1; PSMA2; PSMA3; PSMA4; PSMA6;PSMA7; PSMB10; PSMB1; PSMB4; PSMB5; PSMB6; PSMB7; PSMB8; PSMB9; PSMC1;PSMC2; PSMC3; PSMC3IP; PSMC4; PSMC5; PSMC6; PSMD10; PSMD12; PSMD13;PSMD14; PSMD1; PSMD2; PSMD3; PSMD4; PSMD6; PSMD7; PSMD8; PSMD9; PSME1;PSME2; PSME3; PSME4; PSMF1; PSMG1; PSMG2; PSMG3; PSORS1C1; PSORS1C2;PSPC1; PSPH; PSPN; PSTPIP1; PSTPIP2; PTBP1; PTBP2; PTCD1; PTCH1; PTCHD1;PTCHD4; PTCRA; PTDSS1; PTEN; PTER; PTF1A; PTGDR2; PTGDR; PTGDS; PTGER1;PTGER2; PTGER3; PTGER4; PTGES2; PTGES3; PTGES; PTGIR; PTGIS; PTGR1;PTGS1; PTGS2; PTH1R; PTH2; PTH2R; PTH; PTHLH; PTK2B; PTK2; PTK6; PTK7;PTMA; PTMS; PTN; PTOV1; PTP4A1; PTP4A3; PTPMT1; PTPN11; PTPN12; PTPN13;PTPN14; PTPN18; PTPN1; PTPN21; PTPN22; PTPN23; PTPN2; PTPN3; PTPN4;PTPN5; PTPN6; PTPN7; PTPN9; PTPRA; PTPRB; PTPRCAP; PTPRD; PTPRE; PTPRG;PTPRH; PTPRD; PTPRK; PTPRM; PTPRN2; PTPRN; PTPRO; PTPRQ; PTPRR; PTPRS;PTPRT; PTPRZ1; PTRF; PTRH1; PTRH2; PTRHD1; PTS; PTTG1; PTTG1IP; PTTG2;PTX3; PUF60; PUM2; PURA; PURB; PUS10; PUS1; PVALB; PVR; PVRL1; PVRL2;PVRL3; PVRL4; PWP2; PWWP2B; PXDN; PXDNL; PXK; PXMP2; PXN; PXT1; PYCARD;PYCR1; PYDC1; PYDC2; PYGB; PYGL; PYGM; PYGO1; PYGO2; PYHIN1; PYRDXD1;PYY; PZP; QARS; QDPR; QKI; QPCTL; QPRT; QRFP; QRFPR; QRSL1; QSOX1;QSOX2; QTRT1; R3HCC1; R3HCC1L; R3HDM1; R3HDML; RAB11A; RAB11B;RAB11FIP1; RAB11FIP2; RAB11FIP3; RAB11FIP4; RAB11FIP5; RAB12; RAB14;RAB15; RAB18; RAB1A; RAB1B; RAB20; RAB21; RAB22A; RAB23; RAB24; RAB25;RAB27A; RAB27B; RAB28; RAB29; RAB2A; RAB31; RAB32; RAB33B; RAB34; RAB35;RAB36; RAB37; RAB38; RAB39A; RAB39B; RAB3A; RAB3D; RAB3GAP1; RAB3GAP2;RAB3IL1; RAB3IP; RAB40AL; RAB40B; RAB40C; RAB4A; RAB4B; RAB5A; RAB5B;RAB5C; RAB6A; RAB6B; RAB6C; RAB7A; RAB8A; RAB8B; RAB9A; RABAC1; RABEP1;RABEP2; RABEPK; RABGAP1L; RABGEF1; RABIF; RABL6; RAC1; RAC2; RAC3;RACGAP1; RAD17; RAD18; RAD1; RAD21; RAD21L1; RAD23A; RAD23B; RAD50;RAD51AP1; RAD51B; RAD51C; RAD51D; RAD51; RAD52; RAD54B; RAD9A; RAD9B;RAE1; RAET1E; RAET1L; RAF1; RAG1; RAG2; RAI14; RAI1; RAI2; RALA; RALB;RALBP1; RALGAPA1; RALGAPA2; RALGAPB; RALGDS; RALDPS1; RALY; RALYL;RAMP1; RAMP2; RAMP3; RANBP10; RANBP17; RANBP1; RANBP2; RANBP3; RANBP3L;RANBP6; RANBP9; RANDAP1; RANDRF; RAN; RAP1B; RAP1GAP2; RAP1DS1; RAP2A;RAP2B; RAPDEF1; RAPDEF2; RAPDEF3; RAPDEF4; RAPDEF5; RAPH1; RAPSN; RARA;RARB; RAH; RARRES1; RARRES2; RARRES3; RARS2; RARS; RASA1; RASA2; RASAL1;RASAL2; RASD1; RASD2; RASEF; RASGEF1A; RASGEF1C; RASGRF1; RASGRF2;RASGRP1; RASGRP2; RASGRP3; RASGRP4; RASIP1; RASL10A; RASL10B; RASL11A;RASL11B; RASL12; RASSF1; RASSF2; RASSF3; RASSF4; RASSF5; RASSF6; RASSF7;RASSF8; RAX2; RAX; RB1CC1; RB1; RBAK; RBBP5; RBBP6; RBBP7; RBBP8; RBBP9;RBCK1; RBFOX1; RBFOX2; RBFOX3; RBL1; RBL2; RBM10; RBM12; RBM14;RBM14-RBM4; RBM15; RBM17; RBM20; RBM25; RBM25; RBM27; RBM28; RBM38;RBM39; RBM3; RBM45; RBM46; RBM47; RBM4; RBM5; RBM6; RBM7; RBMS1; RBMS2;RBMS3; RBMX2; RBMX; RBMXL2; RBMY1A1; RBP1; RBP2; RBP3; RBP4; RBPJ;RBPMS2; RBSN; RBX1; RC3H1; RCAN1; RCAN2; RCBTB1; RCBTB2; RCHY1; RCL1;RCN1; RCN2; RCOR1; RCSD1; RCVRN; RD3; RDH10; RDH11; RDH12; RDH14; RDH16;RDH5; RDH8; RDM1; RDX; REC8; RECK; RECQL5; RECQL; REEP1; REEP2; REEP3;REEP5; REEP6; REG1A; REG1B; RED3A; RELA; RELB; REL; RELN; REM1; RENBP;REN; REPS1; REPS2; RERG; RERGL; REST; RET; RETN; RETNLB; RETSAT; REVI;REV3L; REXO1; REXO2; REXO4; RFC1; RFC2; RFC3; RFC4; RFC5; RFFL; RFK;RFPL1; RFT1; RFTN1; RFTN2; RFWD2; RFWD3; RFX1; RFX2; RFX3; RFX4; RFX5;RFX6; RFX8; RFXANK; RFXAP; RGCC; RGL1; RGL2; RGL4; RGMA; RGMB; RGN;RGPD2; RGR; RGS10; RGS11; RGS12; RGS13; RGS14; RGS16; RGS17; RGS18;RGS19; RGS1; RGS20; RGS21; RGS22; RGS2; RGS3; RGS4; RGS5; RGS6; RGS7BP;RGS7; RGS8; RGS9BP; RGS9; RGSL1; RHAG; RHBDD2; RHBDD3; RHBDF1; RHBDF2;RHBDL1; RHBDL2; RHCE; RHCG; RHEB; RHEBL1; RHNO1; RHOB; RHOBTB1; RHOBTB2;RHOBTB3; RHOD; RHOF; RHOG; RHOH; RHO; RHOJ; RHOQ; RHOT1; RHOU; RHOV;RHOXF1; RHOXF2; RHPN1; RHPN2; RIBC2; RIC1; RIC3; RICTOR; RIF1; RILP;RILPL1; RIMBP2; RIMBP3C; RIMS1; RIMS2; RIMS4; RIN1; RIN2; RIN3; RING1;RINT1; RIOK1; RIOK2; RIOK3; RIPK1; RIPK2; RIPK3; RIPK4; RIPPLY2; RIT1;RIT2; RITA1 ; RLBP1; RLF; RLIM; RLN1; RLN2; RLN3; RMDN1; RMDN2; RMDN3;RMI1; RMI2; RMND1; RNASEI1; RNASEI2; RNASEI3; RNASE1; RNASE2; RNASE3;RNASE4; RNASE6; RNASE7; RNASE8; RNASE9; RNASEH1; RNASEH2A; RNASEH2B;RNASEH2C; RNASEK; RNASEL; RNASET2; RND1; RND3; RNF103-CHMP3; RNF103;RNF111; RNF112; RNF114; RNF123; RNF125; RNF128; RNF130; RNF135; RNF138;RNF139; RNF144A; RNF144B; RNF145; RNF149; RNF14; RNF150; RNF152; RNF157;RNF167; RNF168; RNF170; RNF180; RNF182; RNF19A; RNF207; RNF20; RNF213;RNF214; RNF215; RNF24; RNF2; RNF31; RNF34; RNF39; RNF40; RNF41; RNF43;RNF44; RNF4; RNF5; RNF6; RNF7; RNF8; RNGTT; RNH1; RNLS; RNMT; RNPEP;RNPEPL1; RNPS1; ROBO1; ROBO2; ROBO3; ROBO4; ROCK1; ROCK2; ROGD1; ROM1;ROPN1B; ROPN1; ROPN1L; ROR1; ROR2; RORA; RORB; RORC; ROS1; RP1; RP1L1;RP2; RP9; RPA1; RPA2; RPA3; RPA4; RPAIN; RPAP1; RPE; RPGR; RPGRIP1;RPGRIP1L; RPH3A; RPH3AL; RPIA; RPL10A; RPL10; RPL10L; RPL12; RPL13;RPL14; RPL15; RPL17-C18orf32; RPL17; RPL18; RPL19; RPL21; RPL23A; RPL23;RPL24; RPL27A; RPL29; RPL30; RPL31; RPL34; RPL35; RPL36A; RPL36AL;RPL37A; RPL38; RPL39; RPL39L; RPL3; RPL41; RPL4; RPL6; RPL7A; RPL7;RPLP0; RPLP1; RPN1; RPN2; RPP14; RPP21; RPP25; RPP38; RPP40; RPRD1A;RPRD1B; RPRD2; RPRM; RPS10; RPS14; RPS15A; RPS16; RPS18; RPS19BP1;RPS20; RPS24; RPS27A; RPS27; RPS27L; RPS29; RPS2; RPS3A; RPS3; RPS4X;RPS4Y1; RPS6KA2; RPS6KA3; RPS6KA4; RPS6KA5; RPS6KA6; RPS6KB1; RPS6KB2;RPS9; RPSA; RPTOR; RQCD1; RRAD; RRAGA; RRAS2; RRAS; RRBP1; RREB1; RRH;RRM1; RRM2B; RRM2; RRN3; RRNAD1; RRP1B; RRP1; RRP9; RRS1; RS1; RSAD2;RSF1; RSL1D1; RSL24D1; RSPH1; RSPH4A; RSPH9; RSPO2; RSPO3; RSPO4; RSRC1;RSRC2; RSRP1; RSU1; RTCB; RTEL1; RTKN2; RTKN; RTL1; RTN1; RTN2; RTN3;RTN4; RTN4IP1; RTN4R; RTP3; RTP4; RTTN; RUFY1; RUFY3; RUNDC3B; RUNX1;RUNXIT1; RUNX2; RUNX3; RUVBL1; RUVBL2; RXFP1; RXFP2; RXFP3; RXRA; RXRB;RXRD; RYBP; RYK; RYR1; RYR2; RYR3; S1000A10; S100A11; S100A12; S100A13;S100A14; S100A16; S100A1; S100A2; S100A3; S100A4; S100A5; S100A6;S100A7A; S100A7; S100A8; S100A9; S100B; S100P; S100Z; S1PR2; S1PR3;S1PR4; S1PR5; SAA1; SAA2; SAA4; SAAL1; SACM1L; SACS; SAE1; SAFB2; SAFB;SAGE1; SAG; SALL1; SALL2; SALL3; SALL4; SAMD14; SAMD1; SAMD4A; SAMD5;SAMD9; SAMD9L; SAMHD1; SAMM50; SAMSN1; SAP30BP; SAP30L; SAPCD1; SAPCD2;SAR1A; SAR1B; SARDH; SARM1; SARNP; SARS2; SART1; SART3; SASH1; SASH3;SAT1; SAT2; SATB1; SATB2; SATL1; SAV1; SBDS; SBF1; SBF2; SBNO1; SBNO2;SBSN; SC5D; SCAF11; SCAF1; SCAF4; SCAF8; SCAI; SCAMP2; SCAMP5; SCAPER;SOAP; SCARA3; SCARA5; SCARB1; SCARB2; SCARF2; SCCPDH; SCD5; SCD; SCFD1;SCFD2; SCG2; SCG3; SCG5; SCGB1A1; SCGB1D1; SCGB1D2; SCGB2A1; SCGB2A2;SCGB2B2; SCGB3A1; SCGB3A2; SCGN; SCHIP1; SCIN; SCLT1; SCLY; SCML2;SCML4; SCN10A; SCN11A; SCN1A; SCN1B; SCN2A; SCN2B; SCN3A; SCN3B; SCN4A;SCN4B; SCN5A; SCN7A; SCN8A; SCN9A; SCNM1; SCNN1A; SCNN1B; SCNN1D;SCNN1G; SCO1; SCO2; SCP2D1; SCPEP1; SCRIB; SCRN1; SCT; SCTR; SCUBE1;SCUBE2; SCUBE3; SCYL1; SCYL3; SDC1; SDC2; SDC3; SDC4; SDCBP2; SDCBP;SDCCAG3; SDCCAG8; SDF2; SDF2L1; SDF4; SDHAF1; SDHAF2; SDHAF4; SDHA;SDHC; SHD; SDK1; SDK2; SDPR; SDR42E1; SDR9C7; SDS; SEC11A; SEC11C;SEC13; SEC14L1; SEC14L2; SEC14L3; SEC16B; SEC23A; SEC23B; SEC23IP;SEC24A; SEC24B; SEC24C; SEC31A; SEC61A1; SEC61G; SEC62; SEC63; SECISBP2;SECISBP2L; SECTM1I SEL1L; SELE; SELENBP1; SELL; SELP; SELPLG; SEMA3A;SEMA3B; SEMA3C; SEMA3D; SEMA3E; SEMA3F; SEMA3G; SEMA4A; SEMA4B; SEMA4D;SEMA4F; SEMA4G; SEMA5A; SEMA5B; SEMA6A; SEMA6B; SEMA6D; SEMA7A; SEMG1;SEMG2; SENP1; SENP2; SENP3; SENP5; SENP6; SENP8; SEPHS1; SEPSECS;SERAC1; SERF1A; SERGEF; SERINCI; SERINC3; SERINC5; SERP1; SERP2;SERPINA10; SERPINA11; SERPINA12; SERPINA1; SERPINA3; SERPINA4; SERPINA5;SERPINA6; SERPINA7; SERPINA9; SERPINB10; SERPINB13; SERPINB1; SERPINB2;SERPINB3; SERPINB4; SERPINB5; SERPINB6; SERPINB7; SERPINB8; SERPINB9;SERPINC1; SERPIND1; SERPINE1; SERPINE2; SERPINE3; SERPINF1; SERPINF2;SERPING1; SERPINH1; SERPINI1; SERPINI2; SERTAD1; SERTAD2; SESN1; SESN3;SETBP1; SETD1A; SETD1B; SETD2; SETD3; SETD5; SETD7; SETD8; SETDB2; SET;SETMAR; SETX; SEZ6; SEZ6L2; SEZ6L; SF1; SF3A1; SF3B1; SF3B2; SF3B6;SF11; SFMBT1; SFMBT2; SFR1; SFRP1; SFRP2; SFRP4; SFRP5; SFSWAP; SFT2D2;SFT2D3; SFTA2; SFTA3; SFTPA1; SFTPA2; SFTPB; SFTPC; SFTPD; SFXN1; SFXN2;SFXN4; SGCA; SGCB; SGCD; SGCE; SGCG; SGCZ; SGIP1; SGK1; SGK223; SGK2;SGK3; SGMS1; SGMS2; SGOL1; SGPL1; SGPP1; SGPP2; SGSH; SGSM2; SGSM3;SGTA; SH2B1; SH2B2; SH2B3; SH2D1A; SH2D2A; SH2D3A; SH2D3C; SH2D4A;SH2D4B; SH3BGR; SH3BGRL2; SH3BGRL; SH3BP1; SH3BP2; SH3BP4; SH3BP5;SH3D19; SH3GL1; SH3GL2; SH3GL3; SH3KBP1; SH3PXD2A; SH3PXD2B; SH3RF1;SH3RF3; SH3TC2; SH3YL1; SHANK1; SHANK2; SHANK3; SHARPIN; SHBG; SHB;SHC1; SHC2; SHC3; SHC4; SHCBP1; SHF; SHFM1; SHH; SHISA2; SHISA3; SHISA6;SHISA9; SHMT1; SHMT2; SHOC2; SHOX2; SHOX; SHPK; SHPRH; SHQ1; SHROOM2;SHROOM3; SHROOM4; SIAE; SIAH1; SIAH2; SIDT1; SIGIRR; SIGLEC11; SIGLEC14;SIGLEC1; SIGLEC5; SIGLEC7; SIGLEC8; SIGLEC9; SIGMAR1; SI; SIK1; SIK2;SIK3; SIL1; SIM1; SIM2; SIN3A; SIN3B; SIPA1; SIPA1L2; SIPA1L3; SIRPA;SIRPB1; SIRPG; SIRT1; SIRT2; SIRT3; SIRT4; SIRT5; SIRT6; SIRT7; SIT1;SIVA1; SIX1; SIX2; SIX3; SIX4; SIX5; SIX6; SKA1; SKA2; SKAP1; SKAP2;SKIL; SKIV2L2; SKIV2L; SKDR1; SKDR2; SKP1; SKP2; SLA2; SLA; SLAIN2;SLAMF1; SLAMF6; SLAMF7; SLAMF8; SLBP; SLC10A1; SLC10A2; SLC10A6;SLC10A7; SLC11A1; SLC11A2; SLC12A1; SLC12A2; SLC12A3; SLC12A4; SLC12A5;SLC12AD; SLC12A7; SLC12AB; SLC12A9; SLC13A1; SLC13A2; SLC13A3; SLC13A5;SLC14A1; SLC14A2; SLC15A1; SLC15A2; SLC15A4; SLC16A10; SLC16A11;SLC16A12; SLC16A13; SLC16A1; SLC16A2; SLC16A3; SLC16A6; SLC16A7;SLC16A8; SLC16A9; SLC17A1; SLC17A2; SLC17A3; SLC17A4; SLC17A5; SLC17A6;SLC17A7; SLC17A8; SLC18A1; SLC18A2; SLC18A3; SLC19A1; SLC19A2; SLC19A3;SLC1A1; SLC1A2; SLC1A3; SLC1A4; SLC1A5; SLC1A6; SLC20A1; SLC20A2;SLC22A11; SLC22A12; SLC22A13; SLC22A14; SLC22A16; SLC22A17; SLC22A18AS;SLC22A18; SLC22A1; SLC22A23; SLC22A24; SLC22A2; SLC22A3; SLC22A4;SLC22A5; SLC22A6; SLC22A7; SLC22A8; SLC23A1; SLC23A2; SLC24A1; SLC24A2;SLC24A3; SLC24A4; SLC24A5; SLC25A10; SLC25A12; SLC25A13; SLC25A14;SLC25A15; SLC25A16; SLC25A18; SLC25A19; SLC25A1; SLC25A20; SLC25A21;SLC25A22; SLC25A23; SLC25A25; SLC25A27; SLC25A2; SLC25A36; SLC25A37;SLC25A38; SLC25A3; SLC25A40; SLC25A41; SLC25A42; SLC25A43; SLC25A45;SLC25A46; SLC25A47; SLC25A4; SLC25A52; SLC25A5; SLC25A6; SLC26A1;SLC26A2; SLC26A3; SLC26A4; SLC26A5; SLC26A6; SLC26A7; SLC26A8; SLC26A9;SLC27A1; SLC27A2; SLC27A3; SLC27A4; SLC27A5; SLC28A1; SLC28A2; SLC28A3;SLC29A1; SLC29A2; SLC29A3; SLC29A4; SLC2A10; SLC2A11; SLC2A12; SLC2A13;SLC2A14; SLC2A2; SLC2A3; SLC2A4RG; SLC2A5; SLC2A6; SLC2A8; SLC2A9;SLC30A10; SLC30A1; SLC30A3; SLC30A4; SLC30A5; SLC30A6; SLC30A7; SLC30A8;SLC30A9; SLC31A1; SLC31A2; SLC32A1; SLC33A1; SLC34A1; SLC34A2; SLC34A3;SLC35A1; SLC35A2; SLC35A3; SLC35A4; SLC35B2; SLC35B4; SLC35C1; SLC35D3;SLC35F1; SLC35F2; SLC35F3; SLC35F4; SLC35F6; SLC35G1; SLC35G2; SLC35G5;SLC35G6; SLC36A1; SLC36A2; SLC37A1; SLC37A2; SLC37A4; SLC3BA1; SLC3BA2;SLC3BA4; SLC3BA5; SLC3BA6; SLC3BA7; SLC3BA8; SLC3BA9; SLC39A10;SLC39A11; SLC39A12; SLC39A13; SLC39A14; SLC39A1; SLC39A2; SLC39A3;SLC39A4; SLC39A6; SLC39A7; SLC39A8; SLC39A9; SLC3A1; SLC3A2; SLC40A1;SLC41A1; SLC43A1; SLC43A2; SLC43A3; SLC44A1; SLC44A2; SLC44A4; SLC44A5;SLC45A2; SLC45A3; SLC45A4; SLC46A1; SLC46A2; SLC47A1; SLC48A1; SLC4A10;SLC4A11; SLC4A1AP; SLC4A1; SLC4A2; SLC4A3; SLC4A4; SLC4A5; SLC4A7;SLC4A9; SLC50A1; SLC5IA; SLC5113; SLC52A1; SLC52A2; SLC52A3; SLC5A11;SLC5Al2; SLC5A1; SLC5A2; SLC5A3; SLC5A4; SLC5A5; SLC5AD; SLC5A7;SLC5A8B; SLC6A11; SLC6A12; SLC6A13; SLC6A14; SLC6A15; SLC6A18; SLC6A19;SLC6A1; SLC6A20; SLC6A2; SLC6A4; SLC6A5; SLC6A6; SLC6A7; SLC6A8; SLC6A9;SLC7A10; SLC7A11; SLC7A13; SLC7A14; SLC7A1; SLC7A2; SLC7A3; SLC7A4;SLC7A5; SLC7A6; SLC7A7; SLC7A8; SLC7A9; SLC8A1; SLC8A2; SLC8A3; SLC9A1;SLC9A2; SLC9A3; SLC9A3R1; SLC9A3R2; SLC9A4; SLC9A5; SLC9A6; SLC9A7;SLC9A8; SLC9A9; SLC9B1; SLC9B2; SLC9C1; SLC9C2; SLCP1A2; SLCO1B1;SLCO1B3; SLCO1B7; SLCO1C1; SLCO2A1; SLCO2B1; SLCO3A1; SLCO4A1; SLCO4C1;SLCO5A1; SLCO6A1; SLFN12; SLFN12L; SLFN14; SLFN5; SLIT1; SLIT2; SLIT3;SLITRK1; SLITRK2; SLITRK3; SLITRK5; SLITRK6; SLK; SLMAP; SLMO2; SLN;SLP1; SLIM; SLU7; SLURP1; SLX4; SLX4IP; SMAD1; SMAD2; SMAD3; SMAD4;SMAD5; SMAD6; SMAD7; SMAD9; SMAGP; SMAP1; SMARCA1; SMARCA2; SMARCA4;SMARCA5; SMARCAD1; SMARCAL1; SMARCB1; SMARCC1; SMARCC2; SMARCD1;SMARCD3; SMARCE1; SMC1A; SMC1B; SMC2; SMC3; SMC4; SMC5; SMCD; SMCHD1;SMCD4; SMCP; SMEK1; SMEK2; SK1; SMG6; SMG8; SMIM15; SMIM19; SMIM20;SMIM21; SMIM23; SMIM5; SMN2; SMOC1; SMOC2; SMO; SMOX; SMPD1; SMPD2;SMPD3; SMPDL3A; SMPDL3B; SMPX; SMR3B; SMS; SMTN; SMTNL1; SMU1; SMUG1;SMURF1; SMURF2; SMYD1; SMYD2; SMYD3; SMYD4; SMYD5; SNAI1; SNAI2; SNAI3;SNAP23; SNAP25; SNAP29; SNAP47; SNAP91; SNAPC1; SNAPC4; SNAPC5; SNCA;SNCAIP; SNOB; SNCL; SND1; SNED1; SNF8; SNIP1; SNRK; SNRNP200; SNRNP27;SNRNP70; SNRPA; SNRPB; SNRPC; SNRPD1; SNRPD3; SNRPE; SNRPF; SNRPN;SNTA1; SNTB1; SNTG1; SNTG2; SNUPN; SNURF; SNW1; SNX10; SNX12; SNX14;SNX16; SNX18; SNX19; SNX1; SNX20; SNX24; SNX25; SNX29; SNX2; SNX30;SNX3; SNX5; SNX9; SDAT1; SDAT2; SDBP; SOCS1; SOCS2; SOCS3; SOCS4; SOCS5;SOCS6; SOCS7; SOD2; SOD3; SOHLH1; SOHLH2; SON; SDRBS1; SDRBS2; SDRBS3;SORCS1; SORCS2; SORCS3; SORD; SURL1; SOS1; SOS2; SOSTDC1; SOST; SOX10;SOX11; SOX12; SOX13; SOX14; SOX15; SOX17; SOX18; SOX1; SOX21; SOX2;SOX3; SOX4; SOX5; SOX6; SOX7; SOX8; SOX9; SP100; SP110; SP140; SP1; SP2;SP3; SP4; SP5; SP6; SP7; SP8; SPA17; SPACA1; SPACA3; SPAG11A; SPAG11B;SPAG16; SPAG1; SPAG4; SPAG5; SPAG6; SPAG7; SPAG8; SPAG9; SPAM1; SPANXA2;SPANXB1; SPANXD; SPANXN4; SPARC; SPARCL1; SPAST; SPATA13; SPATA16;SPATA17; SPATA18; SPATA19; SPATA20; SPATA21; SPATA22; SPATA25; SPATA2;SPATA5; SPATA7; SPATA8; SPATA9; SPATC1; SPC24; SPC25; SPCS3; SPDEF;SPDL1; SPDYA; SPECC1; SPECC1L; SPEF2; SPEC; SPESP1; SPG11; SPG20; SPG21;SPG7; SPHK1; SPHK2; SPHKAP; SPI1; SPIB; SPIC; SPIDR; SPIN1; SPIN2A;SPINK1; SPINK2; SPINK4; SPINK5; SPINK6; SPINK7; SPINT1; SPINT2; SPNS1;SPNS2; SPIN; SPOCK1; SPOCK2; SPOCK3; SPON1; SPON2; SPUP; SPP1; SPP2;SPPL2A; SPPL2B; SPPL2C; SPPL3; SPRED1; SPRED2; SPRED3; SPR; SPRN;SPRR1A; SPRR1B; SPRR2A; SPRR2B; SPRR3; SPRTN; SPRY1; SPRY2; SPRY3;SPRY4; SPRYD7; SPSB3; SPSB4; SPTA1; SPTAN1 ; SPTB; SPTBN1; SPTBN2;SPTBN4; SPTBN5; SPTLC1; SPTLC2; SPTLC3; SPTSSB; SPTY2D1; SPZ1; SQLE;SQRDL; SQSTM1; SRA1; SRBD1; SRCAP; SRC; SRCIN1; SRD5A1; SRD5A2; SRD5A3;SREBF1; SREBF2; SREK1; SREK1IP1; SRFBP1; SRF; SRGAP1; SRGAP2; SRGAP3;SRGN; SRI; SRL; SRMS; SRP14; SRP19; SRP68; SRP72; SRP9; SRPK1; SRPK2;SRPRB; SRPR; SRPX2; SRPX; SRR; SRRM1; SRRM2; SRRM4; SRRT; SRSF10;SRSF11; SRSF12; SRSF1; SRSF2; SRSF3; SRSF4; SRSF5; SRSF6; SRSF7; SRSF9;SRXN1; SRY; SS18; SS18L1; SSB; SSBP1; SSBP2; SSFA2; SSH1; SSH2; SSMEM1;SSNA1; SSPN; SSPD; SSR1; SSR2; SSRP1; SSSCA1; SST; SSTR1; SSTR2; SSTR3;SSTR4; SSTR5; SSUH2; SSX1; SSX2B; SSX2IP; SSX4B; SSX5; ST13; ST14; ST18;ST20; ST3GAL1; ST3GAL2; ST3GAL4; ST3GAL5; ST3GAL6; ST5; ST6GAL1;ST6GAL2; ST6GALNAC1; ST6GALNAC2; ST6GALNAC4; ST6GALNAC6; ST7; ST7L;ST8SIA1; ST8SIA2; ST8SIA3; ST8SIA4; ST8SIA6; STAB1; STAB2; STAC3; STAG;STAG1; STAG2; STAG3; STAM2; STAMBP; STAMBPL1; STAM; STAP1; STAP2;STARD10; STARD13; STARD3; STARD3NL; STARD5; STARD7; STARD8; STARD9;STAR; STAT1; STAT2; STAT3; STAT4; STAT5A; STAT5B; STAT6; STATH; STAU2;STBD1; STC1; STC2; STEAP1; STEAP2; STEAP3; STEAP4; STH; STIL; STIM1;STIM2; STIP1; STK10; STK11; STK11IP; STK17A; STK17B; STK19; STK24;STK25; STK26; STK31; STK32A; STK32B; STK32C; STK33; STK35; STK38L;STK39; STK3; STK4; STMN2; STMN3; STMN4; STOM; STOML1; STDML2; STDML3;STON1-GTF2A1L; STON1; STOX1; STRA13; STRA6; STRA8; STRADA; STRAD8;STRAP; STRC; STRN3; STRN4; STRN; STS; STT3A; STT3B; STUB1; STX11; STX16;STX17; STX18; STX1A; STX1B; STX2; STX3; STX4; STX5; STX6; STX8; STXBP1;STXBP2; STXBP4; STXBP5; STXBP5L; STXBP6; STYK1; STYX; SUB1; SUCLA2;SUCLG1; SUCLG2; SUCNR1; SUCO; SUDS3; SUFU; SUGCT; SUGP1; SUGT1; SULF1;SULF2; SULT1A1; SULT1A2; SULT1A4; SULT1B1; SULT1C2; SULT1E1; SULT2A1;SULT2B1; SULT4A1; SUMF1; SUMF2; SUMO1; SUMO2; SUMO3; SUMO4; SUN1; SUN2;SUN3; SUOX; SUPT2OH; SUPT3H; SUPT4H1; SUPT7L; SUPV3L1; SURF1; SURF4;SUSD1; SUSD2; SUSD4; SUV39H1; SUV39H2; SUV420H2; SUZ12; SV2B; SV2C;SVEP1; SVIL; SVIP; SVOP; SWAP70; SWT1; SYBU; SYCE1; SYCE1L; SYCP2;SYCP2L; SYCP3; SYK; SYMPK; SYN1; SYN2; SYN3; SYNCRIP; SYNDIG1; SYNE1;SYNE2; SYNE4; SYNGAP1; SYNGR1; SYNGR2; SYNJ1; SYNJ2BP; SYNJ2; SYNM;SYNPO2; SYNPO; SYNPR; SYP; SYPL1; SYPL2; SYT11; SYT12; SYT13; SYT14;SYT1; SYT4; SYT6; SYT9; SYTL1; SYTL2; SYTL5; SYVN1; TAAR1; TAAR2; TAAR5;TAAR6; TAB1; TAB2; TAB3; TAC4; TACC1; TACC2; TAC4; TACC3; TAC01; TACR1;TACR2; TACR3; TADA1; TADA2A; TADA3; TAF15; TAF1B; TAF1C; TAF1D; TAF1;TAF2; TAF3; TAF4B; TAF4; TAF5L; TAF6; TAF7; TAF7L; TAF8; TAF9; TAGAP;TAGLN2; TAGLN; TAL1; TAL2; TALD01; TAMM41; TANC1; TANC2; TANGO2; TANK;TAOK1; TAOK2; TAOK3; TAP1; TAP2; TAPBP; TAPBPL; TARBP1; TARBP2; TARP;TARS; TARSL2; TAS2R10; TAS2R13; TAS2R14; TAS2R16; TAS2R1; TAS2R38;TAS2R50; TAS2R60; TAS2R9; TASP1; TATDN1; TAT; TAX1BP1; TAX1BP3; TAZ;TBATA; TBC1D15; TBC1D16; TBC1D1; TBC1D20; TBC1D22A; TBC1D22B; TBC1D24;TBC1D25; TBC1D2; TBC1D2; TBC1D3C; TBC1D3F; TBC1D4; TBC1D5; TBC1D7;TBC1D8; TBC1D9; TBCA; TBCC; TBCD; TBCE; TBCEL; TBK1; TBKBP1; TBL1X;TBKBP1; TBL1X; TBK1XR1; TBL1; TBL2; TBL3; TBP; TBPL1; TBPL2; TBR1;TBRG1; TBX10; TBX18; TBX19; TBX1; TBX20; TBX21; TBX22; TBX2; TBX3; TBX4;TBX5; TBX6; TBXA2R; TBXAS1; TCAIM; TCAP; TCEA1; TCEA2; TCEA3; TCEAL1;TCEAL2; TCEAL4; TCEAL7; TCEB1; TCEB2; TCEB3C; TCERG1; TCERG1L; TCF12;TCF15; TCF19; TCF20; TCF21; TCF25; TCF3; TCF4; TCF7; TCF7L1; TCF7L2;TCFL5; TCHH; TCHP; TCIRG1; TCL1A; TCL1B; TCN1; TCN2; TCOF1; TCP10;TCP10L2; TCP11L1; TCP1; TETA; TCTE1; TCTN1; TCTN2; TCTN3; TDGFI; TDG;TDD2; TOPI; TOP2; TDRDI; TDRD3; TDRDS; TORDE; TDRD7; TDRD9; TDRKH; TDRP;TEADI; TEAD2; TEAD3; TEAD4; TEC; TECPR2; TECR; TECRL; TECTA; TEF; TEFM;TEK; TEKT1; TEKT5; TELO2; TENM1; TENM2; TENM3; TENM4; TEP1; TEPP; TERF1;TERF2; TERF2IP; TERT; TESL; TES; TESPA1; TET1; TET2; TET3; TEX101;TEX11; TEX14; TEX15; TEX264; TEX29; TEX30; TEX35; TEX40; TFAM; TFAP2A;TFAP2B; TFAP2C; TFAP4; TFB1M; TFB2M; TFCP2; TFDP1; TFDP2; TFDP3; TFE3;TFEB; TFEC; TFF1; TFF2; TFF3; TFG; TF; TFIP11; TFP12; TFP1; TFPT; TFR2;TFRC; TGFA; TGFB1; TGFB1I1; TGFB2; TGFB3; TGFB1; TGFBR1; TGFBR2;TGFBRAP1; TG; TGIF1; TGIF2-C20orf24; TGIF2; TGIF2LX; TGM1; TGM2; TGM3;TGM4; TGM5; TGM6; TGM7; TGOLN2; TGS1; THADA; THAP10; THAP11; THAP1;THAP2; THAP6; THBD; THBS1; THBS2; THBS3; THBS4; THEG; THEM4; THEM5;THEM6; THEMIS2; THEMIS; THG1L; TH; THNSL1; THNSL2; THOC1; THOC2; THOC5;THOC6; T; THUP1; THPU; THRA; THRB; THRSP; THSD1; THSD4; THSD7A; THYN1;TIA1; TIAF1; TIAL1; TIAM1; TIAM2; TICAM1; TICAM2; TICRR; TIFA; TIGD2;TIGIT; TIMD4; TIMELESS; TIMM10; TIMM17A; TIMM21; TIMM22; TIMM23; TIMM44;TIMM50; TIMM8A; TIMM8B; TIMMDC1; TIMP1; TIMP2; TIMP3; TIMP4; TINAG;TINF2; TIPARP; TIPIN; TIPRL; TIRAP; TJP1; TJP2; TJP3; TK1; TK2; TKT;TKTL1; TKTL2; TLDC1; TLE1; TLE2; TLE3; TLE4; TLE6; TLK1; TLK2; TLL1;TLL2; TLN1; TLN2; TLR10; TLR1; TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8;TLR9; TLX1; TLX2; TLX3; TM4SF1; TM4SF20; TM4SF4; TM4SF5; TM6SF2; TM7SF2;TM9SF2; TM9SF4; TMBIM4; TMBIM6; TMC1; TMC2; TMC3; TMC5; TMC6; TMC8;TMCC1; TMCC2; TMCC3; TMC01; TMC04; TMC05A; TMD10; TMED1; TMED2; TMED3;TMED4; TMED7; TMED7-TICAM2; TMED9; TMEFF1; TMEFF2; TMEM100; TMEM101;TMEM105; TMEM106B; TMEM108; TMEM114; TMEM115; TMEM117; TMEM11; TMEM126A;TMEM127; TMEM128; TMEM132A; TMEM132B; TMEM132C; TMEM32D; TMEM132E;TMEM134; TMEM135; TMEM138; TMEM150B; TMEM151A; TMEM151B; TMEM154;TMEM158; TMEM160; TMEM161B; TMEM163; TMEM165; TMEM169; TMEM170A;TMEM171; TMEM173; TMEM175; TMEM176B; TMEM178A; TMEM182; TMEM183A;TMEM184C; TMEM185A; TMEM187; TMEM189; TMEM189-UBE2V1; TMEM18; TMEM199;TMEM200A; TMEM205; TMEM207; TMEM209; TMEM213; TMEM215; TMEM216; TMEM217;TMEM219; TMEM220; TMEM229A; TMEM231; TMEM233; TMEM237; TMEM241; TMEM244;TMEM245; TMEM259; TMEM25; TMEM261; TMEM27; TMEM2; TMEM30A; TMEM30B;TMEM37; TMEM38A; TMEM38B; TMEM39A; TMEM40; TMEM43; TMEM45A; TMEM47;TMEM508; TMEM55A; TMEM57; TMEM5; TMEM60; TMEM62; TMEM63A; TMEM67;TMEM70; TMEM74B; TMEM79; TMEM87A; TMEM88; TMEM89; TMEM88; TMEM95;TMEM97; TMEM98; TMF1; TMIE; TMIGD2; TMIGD3; TMLHE; TMOD1; TMOD2; TMOD3;TMOD4; TMPO; TMPRSS11A; TMPRSS11B; TMPRSS11D; TMPRSS11E; TMPRSS13;TMPRSS15; TMPRSS2; TMPRSS3; TMPRSS4; TMPRSS6; TMPRSS7; TMPRSS9; TMSB10;TMSB158; TMSB4X; TMTC1; TMTC2; TMTC3; TMX1; TMX2; TMX3; TNC; TNFAIP1;TNFAIP2; TNFAIP3; TNFAIP6; TNFAIP8; TNFAIP8L2; TNFAIP8L3; TNF;TNFRSF10A; TNFRSF10B; TNFRSF10C; TNFRSF10D; TNFRSF11A; TNFRSF11B;TNFRSF12A; TNFRSF13B; TNFRSF13C; TNFRSF14; TNFRSF19; TNFRSF1A; TNFRSF1B;TNFRSF21; TNFRSF68; TNFRSF8; TNFSF10; TNFSF11; TNFSF12; TNFSF12-TNFSF13;TNFSF13B; TNFSF13; TNFSF14; TNFSF15; TNFSF18; TNFSF4; TNFSF8; TNFSF9;TNIK; TNIP1; TNIP2; TNIP3; TNK1; TNK2; TNKS2; TNKS; TNMD; TNNC1; TNN;TNNI1; TNNI2; TNNI3; TNNT1; TNNT2; TNNT3; TNP1; TNP2; TNP01; TNP02;TNP03; TNRC18; TNRC6A; TNRC6B; TNR; TNS1; TNS2; TNS3; TNS4; TNXB; TOB1;TOB2; TOLLIP; TOM1; TOM1L1; TOMM20; TOMM34; TOMM40; TOMM70A; TONSL;TOP1; TOP2A; TOP2B; TOP3A; TOP3B; TOPBP1; TOPORS; TOR1A; TOR1AIP1;TOR1AIP2; TOR1B; TOR2A; TOX2; TOX3; TOX4; TOX; TP53AIP1; TP53BP1;TP53BP2; TP53; TP53I11; TP53I13; TP53I3; TP53INP1; TP53INP2; TP53RK;TP53TG3E; TP63; TP73; TPBG; TPCN1; TPCN2; TPD52; TPD52L1; TPD52L2;TPGS2; TPH1; TPH2; TPI1; TPK1; TPM1; TPM2; TPM3; TPM4; TPMT; TPO; TPP1;TPP2; TPPP2; TPPP3; TPPP; TPRG1; TPR; TPRN; TPSAB1; TPSB2; TPSD1; TPSG1;TPT1I; TPTE2; TPTE; TPX2; TRA2A; TRA2B; TRABD2A; TRABD; TRADD; TRAF1;TRAF2; TRAF3; TRAF3IP1; TRAF3IP2; TRAF4; TRAF5; TRAF6; TRAF7; TRAFD1;TRAK1; TRAK2; TRAM1; TRAM1L1; TRAM2; TRAP1; TRAPPC10; TRAPPC11; TRAPPC1;TRAPPC2; TRAPPC4; TRAPPC9; TRAT1; TRDMT1; TRDN; TREH; TREM1; TREM2;TREML1; TREML2; TRERF1; TREX1; TREX2; TRHDE; TRH; TRHR; TRIAP1; TRIB1;TRIB2; TRIB3; TRIM10; TRIM11; TRIM13; TRIM15; TRIM16; TRIM17; TRIM21;TRIM22; TRIM23; TRIM24; TRIM25; TRIM26; TRIM27; TRIM28; TRIM29; TRIM2;TRIM31; TRIM32; TRIM34; TRIM35; TRIM36; TRIM37; TRIM38; TRIM39; TRIM3;TRIM40; TRIM42; TRIM44; TRIM50; TRIM56; TRIM58; TRIM59; TRIM5; TRIM62;TRIM66; TRIM68; TRIM68; TRIM6-TRIM34; TRIM71; TRIM72; TRIM73; TRIM74;TRIM8; TRIM9; TR10BP; TR10; TRIP10; TRIP11; TRIP13; TRIP4; TRIP6; TRIQK;TRMT10A; TRMT12; TRMT1; TRMT44; TRMT55; TRMU; TRO; TRDVE2; TRPA1; TRPC1;TRPC3; TRPC4AP; TRPC4; TRPC5; TRPC6; TRPC7; TRPM1; TRPM2; TRPM3; TRPM4;TRPM5; TRPM6; TRPM7; TRPM8; TRPS1; TRPV1; TRPV2; TRPV3; TRPV4; TRPV5;TRPV6; TRRAP; TSACC; TSC1; TSC22D1; TSC22D3; TSC22D4; TSC2; TSEN2;TSEN34; TSEN54; TSFM; TSG101; TSGA10; TSHR; TSHZ1; TSHZ2; TSHZ3; TSLP;TSNAX; TSN; TSPAN10; TSPAN11; TSPAN12; TSPAN13; TSPAN14; TSPAN16;TSPAN18; TSPAN31; TSPAN32; TSPAN33; TSPAN4; TSPAN6; TSPAN7; TSPAN8;TSPAN9; TSPEAR; TSP02; TSP0; TSPY10; TSPY1; TSPY3; TSPY4; TSPYL1;TSPYL2; TSPYL4; TSPYL5; TSR1; TSSC1; TSSK1B; TSSK2; TSSK4; TSTA3; TSTD1;TST; TTBK1; TTBK2; TTC12; TTC17; TTC19; TTC1; TTC21B; TTC28; TTC29;TTC37; TTC39A; TTC39B; TTC3; TTC5; TTC6; TTC7A; TTC7B; TTC8; TTC9B;TTC9C; TTC9; TTF1; TTF2; TTI1; TTI2; TTK; TTL; TTL10; TTLL11; TTLL12;TTLL1; TTLL3; TTLL4; TTLL5; TTLL6; TTLL7; TTLL8; TTLL9; TTPA; TTR;TTYH1; TTYH2; TUBA1A; TUBA1B; TUBA1C; TUBA3D; TUBA4A; TUBA8; TUBB1;TUBB2A; TUBB2B; TUBB3; TUBB4A; TUBB4B; TUBB6; TUBB; TUBD1; TUBE1; TUBG1;TUBG2; TUBGCP2; TUBGCP3; TUBGCP4; TUBGCP5; TUBGCP6; TUB; TUFM; TUFT1;TULP1; TULP2; TULP3; TULP4; TUSC1; TUSC2; TUSC3; TUSC5; TUT1; TVP23B;TWF1; TWIST1; TWIST2; TWSG1; TXK; TXLNG; TXN2; TXNDC15; TXNDC16;TXNDC17; TXNDC5; TXN; TXNL1; TXNRD2; TXNRD3NB; TYK2; TYMP; TYMS; TYR;TYRO3; TYROBP; TYRP1; TYSND1; TYW1B; U2AF1; U2AF2; UACA; UAP1; UBA1;UBA2; UBA3; UBA7; UBAC1; UBAC2; UBAP1; UBAP2; UBASH3A; UBASH3B; UBB;UBC; UBD; UBE2A; UBE2B; UBE2C; UBE2D1; UBE2D2; UBE2D3; UBE2E1; UBE2E2;UBE2E3; UBE2G1; UBE2G2; UBE2H; UBE2I; UBE2J1; UBE2K; UBE2L3; UBE2L3;UBE2M; UBE2N; UBE2Q2; UBE2QL1; UBE2R2; UBE2S; UBE2T; UBE2U; UBE2V1;UBE2V2; UBE2Z; UBE3A; UBE3B; UBE3C; UBE4A; UBE4B; UBIAD1; UBL3; UBL4A;UBL5; UBL7; UBLCP1; UBN1; UBOX5; UBP1; UBQLN1; UBQLN2; UBQLNL; UBR1;UBR3; UBR4; UBR5; UBR7; UBTD2; UBTF; UBXN1; UBXN2A; UBXN2B; UBXN4;UCHL1; UCHL3; UCHL5; UCK1; UCK2; UCKL1; UCMA; UCN2; UCN3; UCN; UCP1;UCP2; UCP3; UEVLD; UFD1L; UFL1; UFM1; UGCG; UGDH; UGGT1; UGGT2; UGP2;UGT1A10; UGT1A1; UGT1A3; UGT1A4; UGT1A5; UGT1A6; UGT1A7; UGT1A8; UGT1A9;UGT2A1; UGT2A2; UGT2A3; UGT2B10; UGT2B11; UGT2B15; UGT2B28; UGT2B4;UGT2B7; UGT3A2; UGT8; UHMK1; UHRF1BP1; UHRF1; UHRF2; UIMC1; ULBP1;ULBP2; ULBP3; ULK1; ULK2; ULK3; ULK4; UMOD; UMODL1; UMPS; UNC119;UNC13A; UNC13B; UNC13C; UNC13D; UNC45A; UNC45B; UNC5A; UNC5B; UNC5C;UNC5D; UNC79; UNC93A; UNC93B1; UNG; UPB1; UPF1; UPF2; UPF3A; UPF3B;UPK1A; UPK1B; UPK2; UPK3A; UPP1; UPP2; UPRT; UQCC1; UQCC2; UQCRB;UQCRC1; UQCRC2; UQRFS1; UQCRQ; URB2; URGCP; URI1; URM1; UROC1; UROD;UROS; USB1; USE1; USF1; USF2; USH1C; USH1G; USH2A; USO1; USP10; USP11;USP12; USP13; USP14; USP15; USP17L2; USP17L30; USP18; USP20; USP22;USP25; USP26; USP28; USP2; USP32; USP33; USP36; USP37; USP3; USP40;USP42; USP43; USP44; USP46; USP48; USP49; USP4; USP5; USP6; USP6NL;USP7; USP8; USP9X; USP9Y; USPL1; UST; UTF1; UTP14A; UTP14C; UTP20; UTRN;UTS2B; UTS2; UTS2R; UTY; UVRAG; UVSSA; UXS1; UXT; VAC14; VAMP1; VAMP2;VAMP4; VAMP7; VAMP8; VANGL2; VAPA; VAPB; VARS2; VARS; VASH1; VASH2;VASP; VAT1; VAT1L; VAV1; VAV2; VAV3; VAX1; VAX2; VBP1; VCAN; VCL; VCP;VCX2; VCX3A; VCX3B; VCX; VCY; VDAC1; VDAC2; VDR; VEGFA; VEGFB; VEGFC;VENTX; VEPH1; VEZT; VGF; VGLL1; VGLL2; VGLL3; VGLL4; VHL; VHLL; VIL1;VIM; VIPAS39; VIP; VIPR1; VIPR2; VIT; VKDRC1; VLDLR; VMA21; VMO1; VMP1;VN1R2; VN1R4; VNN1; VNN2; VNN3; VOPP1; VPRBP; VPREB1; VPREB3; VPS11;VPS13A; VPS13B; VPS13C; VPS26A; VPS26; VPS33A; VPS33B; VPS35; VPS36;VPS37A; VPS37B; VPS37C; VPS39; VPS41; VPS4A; VPS4B; VPS51; VPS52; VPS53;VPS54; VPS72; VPS8; VRK1; VRK2; VSIG10; VSIG1; VSIG2; VSIG4; VSNL1;VSTM1; VSX1; VSX2; VTA1; VTCN1; VTI1A; VTI1B; VTN; VWA2; VWA3A; VWA3B;VWA5A; VWA5B1; VWA7; VWA8; VWCE; VWDE; VWF; WAPAL; WARS2; WARS; WASF1;WASF3; WASH1; WAS; WASL; WBP1L; WBP2; WBSCR17; WBSCR22; WDFY2; WDFY4;WDHD1; WDPCP; WDR11; WDR12; WDR17; WDR19; WDR1; WDR20; WDR26; WDR31;WDR34; WDR35; WDR36; WDR37; WDR43; WDR45B; WDR45; WDR46; WDR48; WDR49;WDR4; WDR55; WDR5; WDR60; WDR62; WDR64; WDR66; WDR70; WDR72; WDR74;WDR76; WDR78; WDR7; WDR81; WDR83; WDR86; WDR93; WEE1; WFDC1; WFDC2;WFS1; WHSC1; WHSC1L1; WIF1; WIPF1; WIPF2; WIPF3; WIPI1; WIPI2; WISP1;WISP2; WISP3; WLS; WNK1; WNK2; WNK3; WNK4; WNT10A; WNT10B; WNT11; WNT16;WNT1; WNT2B; WNT2; WNT3A; WNT3; WNT4; WNT5A; WNT5B; WNT6; WNT7A; WNT7B;WNT8A; WNT8B; WNT9A; WNT9B; WRAP53; WRB; WRN; WRNIP1; WSB1; WSCD1;WSCD2; WT1; WTAP; WTIP; WWC1; WWC2; WWDX; WWP1; WWP2; WWTR1; XAB2; XAF1;XAGE1B; XAGE1E; XBP1; XCL1; XCL2; XCR1; XDH; XG; XIAP; XIRP1; XIRP2; XK;XKR4; XKR6; XKR9; XPA; XPC; XPNPEP1; XPNPEP2; XPNPEP3; XPO1; XPO4; XPO5;XPO6; XPO7; XPR1; XRCC1; XRCC2; XRCC3; XRCC4; XRCC5; XRCC6BP1; XRCC6;XRN1; XRN2; XRRA1; XXYLT1; XYLB; XYLT1; XYLT2; YAE1D1; YAP1; YARS2;YBX2; YBX3; YDJC; YEATS4; YES1; YIF1A; YIPF1; YIPF3; YIPF5; YKT6; YLPM1;YME1 L1; YPEL1; YPEL2; YPEL3; YPEL4; YPEL5; YTHDC1; YTHDC2; YWHAB;YWHAE; YWHAG; YWHAH; YWHAQ; YWHAZ; YY1AP1; YY1; ZACN; ZAK; ZAP70; ZAR1;ZAR1L; ZASP; ZBED1; ZBED4; ZBED5; ZBP1; ZBTB10; ZBTB12; ZBTB14; ZBTB16;ZBTB17; ZBTB18; ZBTB20; ZBTB21; ZBTB22; ZBTB24; ZBTB2; ZBTB32; ZBTB33;ZBTB34; ZBTB38; ZBTB41; ZBTB46; ZBTB48; ZBTB49; ZBTB4; ZBTB5; ZBTB7C;ZBTB9; ZC2HC1B; ZC3H10; ZC3H11A; ZC3H12C; ZC3H12D; ZC3H14; ZC3H15;ZC3H3; ZC3H4; ZC3H7A; ZC3H7B; ZC3HAV1; ZC3HC1; ZC4H2; ZCCHC11; ZCCHC12;ZCCHC14; ZCCHC2; ZCCHC3; ZCCHC6; ZCCHC8; ZCRB1; ZCWPW1; ZDBF2; ZDHHC11;ZDHHC12; ZDHHC13; ZDHHC14; ZDHHC15; ZDHHC17; ZDHHC1; ZDHHC2; ZDHHC7;ZDHHC8; ZDHHC9; ZEB1; ZEB2; ZFAND3; ZFAND5; ZFAND6; ZFAT; ZFC3H1; ZFHX2;ZFHX3; ZFHX4; ZFP1; ZFP30; ZFP36; ZFP36L1; ZFP36L2; ZFP37; ZFP42; ZFP57;ZFP64; ZFP82; ZFP91; ZFPM1; ZFPM2; ZFR2; ZFR; ZFX; ZFY; ZFYVE19;ZFYVE21; ZFYVE26; ZFYVE27; ZFYVE28; ZFYVE9; ZG16B; ZGLP1; ZGPAT; ZHX1;ZHX2; ZIC1; ZIC2; ZIC3; ZIC4; ZIC5; ZIK1; ZIM2; ZKSCAN1; ZKSCAN3;ZKSCAN7; ZMAT3; ZMAT4; ZMIZ1; ZMYM2; ZMYM3; ZMYM4; ZMYM5; ZMYND10;ZMYND11; ZMYND8; ZNF106; ; ZNF107; ZNF10; ZNF112; ZNF121; ZNF131;ZNF132; ZNF133; ZNF141; ZNF143; ZNF146; ZNF148; ZNF154; ZNF160; ZNF169;ZNF175; ZNF177; ZNF182; ZNF184; ZNF185; ZNF189; ZNF197; ZNF202; ZNF205;ZNF20; ZNF212; ZNF214; ZNF215; ZNF217; ZNF224; ZNF22; ZNF230; ZNF236;ZNF239; ZNF23; ZNF248; ZNF24; ZNF253; ZNF260; ZNF263; ZNF264; ZNF266;ZNF267; ZNF268; ZNF273; ZNF274; ZNF276; ZNF277; ZNF280B; ZNF280D;ZNF281; ZNF282; ZNF286B; ZNF296; ZNF2; ZNF300; ZNF311; ZNF318; ZNF320;ZNF322; ZNF32; ZNF330; ZNF331; ZNF334; ZNF335; ZNF343; ZNF350; ZNF354A;ZNF35; ZNF365; ZNF366; ZNF367; ZNF382; ZNF383; ZNF384; ZNF385A; ZNF385B;ZNF385D; ZNF391; ZNF395; ZNF398; ZNF407; ZNF410; ZNF415; ZNF419; ZNF41;ZNF423; ZNF430; ZNF432; ZNF433; ZNF438; ZNF443; ZNF444; ZNF44; ZNF451;ZNF45; ZNF462; ZNF469; ZNF483; ZNF490; ZNF492; ZNF496; ZNF501; ZNF507;ZNF512B; ZNF512; ZNF513; ZNF516; ZNF519; ZNF521; ZNF536; ZNF555; ZNF559;ZNF568; ZNF569; ZNF577; ZNF580; ZNF581; ZNF582; ZNF583; ZNF585B; ZNF592;ZNF596; ZNF606; ZNF607; ZNF608; ZNF615; ZNF618; ZNF627; ZNF629; ZNF639;ZNF644; ZNF645; ZNF646; ZNF652; ZNF654; ZNF664; ZNF667; ZNF668; ZNF674;ZNF676; ZNF678; ZNF683; ZNF687; ZNF689; ZNF703; ZNF704; ZNF706; ZNF711;ZNF716; ZNF717; ZNF746; ZNF74; ZNF750; ZNF763; ZNF764; ZNF765; ZNF76;ZNF774; ZNF776; ZNF778; ZNF784; ZNF79; ZNF7; ZNF800; ZNF804A; ZNF804B;ZNF80; ZNF812; ZNF813; ZNF816; ZNF81; ZNF823; ZNF827; ZNF829; ZNF831;ZNF91; ZNF92; ZNF93; ZNF98; ZNFX1; ZNHIT2; ZNHIT3; ZNRD1; ZNRF3; ZP1;ZP4; ZPBP2; ZPLD1; ZPR1; ZRANB3; ZRSR2; ZSCAN18; ZSCAN22; ZSCAN26;ZSCAN31; ZSCAN32; ZSCAN9; ZSWIM2; ZSWIM6; ZW10; ZWILCH; ZWINT; ZYX;ZZEF1; ZZZ3; or a fragment or variant of any of these. These and otherproteins are understood to be therapeutic, as they are meant to treatthe subject by replacing its defective endogenous production of afunctional protein in sufficient amounts. Accordingly, such therapeuticproteins are typically mammalian, in particular human proteins.

It is further preferred that the at least one coding sequence of the RNAof the present invention encodes a peptide or a protein comprising orconsisting of a therapeutic protein, or a fragment or variant thereof,wherein the therapeutic protein is any one selected from the peptides orproteins listed in Table 1, whereby each peptide or protein isrepresented by formula “c1(Peptide or protein or gene) c2(NCBI RefSeqID) c3(Protein SEQ ID NO) c4(RNA SEQ ID NOs) c5(Related disease,disorder or condition)” as defined above.

In Table 1, each peptide or protein as represented by formula“c1(Peptide or protein or gene) c2(NCBI Ref Seq ID) c3(Protein SEQ IDNO) c4(RNA SEQ ID NOs) c5(Related disease, disorder or condition)” asdefined above corresponds to a preferred therapeutic protein as definedherein and provides the abbreviation of the name of the peptide orprotein indicated under feature c1 (“Peptide or protein”) and thedatabase accession number of that peptide or protein under feature c2(“NCBI Ref Seq ID”) in the same entry. Under feature c3 in the sameentry, Table 1 provides the SEQ ID NO: (as comprised in the sequencelisting herein) corresponding to the amino acid sequence of that peptideor protein. Under feature c4 in the same entry, Table 1 provides the SEQID NO: (as comprised in the sequence listing herein) corresponding tothe nucleic acid sequence of preferred RNA's encoding that peptide orprotein. Feature c5 of Table 1 provides one or more disease, disorder orcondition, for the treatment or prevention of which the peptide orprotein identified by features c1 to c4 in the same entry is preferablyused, ID whereby the abbreviations as disclosed under feature c5 are tobe read from the Abbreviation Dictionary for the “Related disease,disorder or condition” as shown in Table C, whereby each abbreviation isdepicted with a specific “Related disease, disorder or condition” inwritten form as described above.

Thus, Table 1 summarizes preferred embodiments of the present invention,wherein each entry (i.e. peptide or protein of the invention asrepresented by the formula “c1(Peptide or protein or gene) c2(NCBIRefSeq ID) c3(Protein SEQ ID NO) c4(RNA SED ID NOs) c5(Related disease,disorder or condition)”) in Table 1 preferably corresponds to apreferred embodiment and wherein Table 1 provides the necessaryinformation concerning the therapeutic protein, the respective databaseentry, the amino acid sequence of the therapeutic protein, the nucleicacid sequences of preferred RNA's encoding the therapeutic protein aswell as one or more disease, disorder or condition, for the treatment orprevention of which the peptide or protein is preferably used.

More preferably, each entry (i.e. peptide or protein of the invention asrepresented by the formula “c1(Peptide or protein or gene) c2(NCBI RefSeq ID) c3(Protein SEQ ID NO) c4(RNA SEQ ID NOs) c5(Related disease,disorder or condition)”) in Table 1 corresponds to a preferredembodiment of the present invention, wherein feature c4 indicates anucleic acid sequence that may be comprised (in its entirety or afragment or variant thereof as defined herein) in the at least onecoding sequence of the RNA according to the invention. That codingsequence encodes the peptide or protein identified in features c1, c2and c3, or a fragment or variant thereof. Feature c5 indicates one ormore disease, disorder or condition, for the treatment or prevention ofwhich the peptide or protein is preferably used, whereby theabbreviations as disclosed under feature c5 are to be read from theAbbreviation Dictionary for the “Related disease, disorder or condition”as shown in Table C, whereby each abbreviation is depicted with aspecific “Related disease, disorder or condition” in written form asdescribed above.

For example, the at least one coding region of the RNA according to theinvention may encode the protein “AASDH” (see Table 1, entry “c1(AASDH)c2(NP_001273597) c3(27) c4(25141, 39198, 52255, 13084, 65312) c5(ar)”),as identified by the NCBI RefSeq ID “NP_001273597” (see c2 of thatentry). The full-length amino acid sequence of AASDH as used herein isdefined by SEQ ID NO: 27 (see c3 of that entry). Preferred nucleic acidsequences (SEQ ID NO: 25141, 39198, 52255, 13084 and 65312) areidentified under c4 of that entry (see c4 of that entry). Hence, in apreferred embodiment, the RNA according to the invention may comprise atleast one coding sequence comprising or consisting of a nucleic acidsequence as identified under c4 of that entry, such as SEQ ID NO: 25141,39198, 52255, 13084 or 65312, or a fragment or variant of any of thesesequences. Preferably, said RNA is used for treatment or prevention,preferably as described herein, for the disease specified under c5,namely for treatment or prevention of “ar” which according to theAbbreviation Dictionary for the “Related disease, disorder or condition”as shown in Table C corresponds to adenocarcinoma (see c5 of thatentry).

Where reference is made herein to a “therapeutic protein according toTable 1”, a “peptide or protein of Table 1” or to a “nucleic acidsequence encoding a therapeutic protein according to Table 1”, it istypically referred to one of the embodiments as defined by any one ofthe entries in Table 1, wherein one of the nucleic acid sequencesspecified under c4 in that entry, or fragments or variants thereof, arepreferably used for treatment or prevention of a disease, disorder orcondition specified under c5 in that entry, taken into considerationformula “c1(Peptide or protein or gene) c2(NCBI Ref Seq ID) c3(ProteinSEQ ID NO) c4(RNA SEQ ID NOs) c5(Related disease, disorder orcondition)” and the Abbreviation Dictionary for c5 in Table C asdescribed above.

It is thus further preferred that the at least one coding sequence ofthe RNA of the present invention encodes a peptide or protein comprisingor consisting of a therapeutic protein, or a fragment or variant of saidtherapeutic protein, wherein the therapeutic protein is a peptide orprotein identified in Table 1, preferably under feature c1, c2 or c3 inTable 1. More preferably, the at least one coding sequence of the RNAaccording to the invention comprises or consists any one of the nucleicacid sequences provided in Table 1, or a fragment or variant of any oneof these sequences, preferably as defined herein.

According to a preferred embodiment, the present invention concerns anRNA comprising at least one coding sequence encoding a peptide orprotein comprising or consisting of a therapeutic protein, or a fragmentor variant of said therapeutic protein, wherein the therapeutic proteinpreferably comprises or consists of any one of the amino acid sequencesdefined in feature c3 of Table 1, or a fragment or variant of any one ofthese sequences. In other words, the at least one coding sequencepreferably encodes a peptide or protein comprising or consisting of atherapeutic protein, wherein the therapeutic protein comprises orconsists of an amino acid sequence selected from the group consisting ofamino acid sequences according to any one of SEQ ID NO: 1 to 13057, or afragment or variant of any one of said amino acid sequences.

The at least one coding sequence of the RNA according to the inventionpreferably comprises or consists of a nucleic acid sequence encoding apeptide or protein comprising or consisting of a full-length therapeuticprotein or a full-length variant of a therapeutic protein as definedherein. The term “full-length therapeutic protein” or “full-lengthvariant of a therapeutic protein” as used herein typically refers to apeptide or protein that substantially comprises the entire amino acidsequence of the reference protein, such as the naturally occuringtherapeutic protein. As used herein, the term “full-length therapeuticprotein” preferably relates to the full-length sequence of a peptide orprotein specified in Table 1. More preferably, the term “full-lengththerapeutic protein” refers to an amino acid sequence as defined by anyone of the SEQ ID NO:'s listed under feature c3 of Table 1 or to anamino acid sequence provided in the NCBI database under the Ref Seq IDspecified under feature c2 of Table 1.

Alternatively, the at least one coding sequence of the RNA according tothe invention may also comprise a nucleic acid sequence encoding apeptide or protein comprising or consisting of a fragment of atherapeutic protein or a fragment of a variant of a therapeutic proteinas defined herein.

In the context of the present invention, a “fragment” of a therapeuticprotein or of a variant thereof may comprise a sequence of a therapeuticprotein or of a variant thereof as defined above, which is, with regardto its amino acid sequence (or its encoded nucleic acid sequence),N-terminally, C-terminally and/or intrasequentially truncated comparedto the reference amino acid sequence, such as the amino acid sequence ofthe naturally occuring protein or a variant thereof (or its encodednucleic acid sequence) or a peptide or protein as specified in Table 1or a variant thereof. Such truncation may occur either on the amino acidlevel or on the nucleic acid level, respectively. A sequence identitywith respect to such a fragment as defined herein therefore preferablyrefers to the entire therapeutic protein or a variant thereof as definedherein or to the entire (coding) nucleic acid sequence of such an atherapeutic protein or of a variant thereof.

According to a preferred embodiment of the invention, the RNA comprisesat least one coding sequence encoding a peptide or protein comprising orconsisting of a variant of a therapeutic protein as defined herein, or afragment of a variant of a therapeutic protein.

In certain embodiments of the present invention, a “variant” of atherapeutic protein or a fragment thereof as defined herein may beencoded by the RNA comprising at least one coding sequence as definedherein, wherein the amino acid sequence encoded by the at least onecoding sequence differs in at least one amino acid residue from thereference amino acid sequence, such as a naturally occuring amino acidsequence or an amino acid sequence as indicated in Table 1. In thiscontext, the “change” in at least one amino acid residue may consist,for example, in a mutation of an amino acid residue to another aminoacid, a deletion or an insertion. More preferably, the term “variant” asused in the context of the amino acid sequence encoded by the at leastone coding sequence of the RNA according to the invention comprises anyhomolog, isoform or transcript variant of a therapeutic protein or afragment thereof as defined herein, wherein the homolog, isoform ortranscript variant is preferably characterized by a degree of identityor homology, respectively, as defined herein.

Preferably, a variant of a therapeutic protein or a fragment thereof maybe encoded by the RNA comprising at least one coding sequence as definedherein, wherein at least one amino acid residue of the amino acidsequence encoded by the at least one coding sequence is substituted.Substitutions, wherein amino acids, which originate from the same class,are exchanged for one another, are called conservative substitutions. Inparticular, these are amino acids having aliphatic side chains,positively or negatively charged side chains, aromatic groups in theside chains or amino acids, the side chains of which can form hydrogenbridges, e.g. side chains which have a hydroxyl function. Byconservative constitution, e.g. an amino acid having a polar side chainmay be replaced by another amino acid having a corresponding polar sidechain, or, for example, an amino acid characterized by a hydrophobicside chain may be substituted by another amino acid having acorresponding hydrophobic side chain (e.g. serine (threonine) bythreonine (serine) or leucine (isoleucine) by isoleucine (lamina)). Inpreferred embodiment, a variant of a therapeutic protein or a fragmentthereof may be encoded by the RNA according to the invention, wherein atleast one amino acid residue of the amino acid sequence encoded by theat least one coding sequence comprises at least one conservativesubstitution compared to a reference sequence, such as the respectivenaturally occuring sequence or a sequence indicated in Table 1. Theseamino acid sequences as well as their encoding nucleic acid sequences inparticular are comprised by the term “variant” as defined herein.

Insertions, deletions and/or non-conservative substitutions are alsopossible, in particular, at those sequence positions, which preferablydo not cause a substantial modification of the three-dimensionalstructure. Modifications to a three-dimensional structure byinsertion(s) or deletion(s) can easily be determined e.g. using CDspectra (circular dichroism spectra) (Urry, 1985, Absorption, CircularDichroism and ORD of Polypeptides, in: Modern Physical Methods inBiochemistry, Neuberger et al. (ed.), Elsevier, Amsterdam).

In order to determine the percentage, to which two sequences (nucleicacid sequences, e.g. RNA or mRNA sequences as defined herein, or aminoacid sequences, preferably the amino acid sequence encoded by the RNAaccording to the invention) are identical, the sequences can be alignedin order to be subsequently compared to one another. For this purpose,e.g. gaps can be inserted into the sequence of the first sequence andthe component at the corresponding position of the second sequence canbe compared. If a position in the first sequence is occupied by the samecomponent as is the case at a corresponding position in the secondsequence, the two sequences are identical at this position. Thepercentage, to which two sequences are identical, is a function of thenumber of identical positions divided by the total number of positions.The percentage, to which two sequences are identical, can be determinedusing a mathematical algorithm. A preferred, but not limiting, exampleof a mathematical algorithm, which can be used is the algorithm ofKarlin et al. (1993), PNAS USA, 90:5873-5877 or Altschul et al. (1997),Nucleic Acids Res., 25:3389-3402. Such an algorithm is integrated, forexample, in the BLAST program. Sequences, which are identical to thesequences of the present invention to a certain extent, can beidentified by this program.

A fragment of a therapeutic protein or a variant thereof encoded by theat least one coding sequence of the RNA according to the invention maytypically comprise an amino acid sequence having a sequence identity ofat least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably ofat least 70%, more preferably of at least 80%, even more preferably atleast 85%, even more preferably of at least 90% and most preferably ofat least 95% or even 97%, with a reference amino acid sequence,preferably with the amino acid sequence of the respective naturallyoccuring full-length therapeutic protein or a variant thereof, morepreferably with the amino acid sequence of a peptide or proteinspecified in Table 1 or a variant thereof.

More preferably, a fragment of a therapeutic protein or a variantthereof encoded by the at least one coding sequence of the RNA accordingto the invention may typically comprise or consist of an amino acidsequence having a sequence identity of at least 5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99%, preferably of at least 70%, more preferablyof at least 80%, even more preferably at least 85%, even more preferablyof at least 90% and most preferably of at least 95% or even 97%, with anamino acid sequence of a protein selected from the peptides or proteinsindicated in Table 1 or a variant thereof. Even more preferably, afragment of a therapeutic protein or a variant thereof encoded by the atleast one coding sequence of the RNA according to the invention maytypically comprise or consist of an amino acid sequence having asequence identity of at least 5%,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99%, preferably of at least 70%, more preferably of at least 80%, evenmore preferably at least 85%, even more preferably of at least 90% andmost preferably of at least 95% or even 97%, with any one of the aminoacid sequences defined in feature c3 of Table 1, or a fragment orvariant of any one of these sequences.

Most preferably, a fragment of a therapeutic protein or a variantthereof encoded by the at least one coding sequence of the RNA accordingto the invention typically comprises or consists of an amino acidsequence having a sequence identity of at least 80% with any one of theamino acid sequences defined in feature c3 of Table 1, or a fragment orvariant of any one of these sequences.

Preferably, the therapeutic protein encoded by the at least one codingsequence of the RNA is a therapeutic protein as defined herein, which isencoded by a nucleic acid sequence comprising or consisting of any oneof the nucleic acid sequences encoding a peptide or protein as definedin features c1, c2 or c3 of every peptide or protein entry of Table 1,or a fragment or variant of any one of these sequences. More preferably,the therapeutic protein is encoded by a naturally occuring nucleic acidsequence comprising or consisting of any one of the nucleic acidsequences encoding a peptide or protein as defined in features c1, c2 orc3 of every peptide or protein entry of Table 1, or a fragment orvariant of any one of these sequences. Even more preferably, thetherapeutic protein is encoded by a nucleic acid sequence comprising orconsisting of any one of the nucleic acid sequences encoding a peptideor protein as defined in features c1, c2 or c3 of every peptide orprotein entry of Table 1, or a fragment or variant of any one of thesesequences, wherein the nucleic acid sequence encoding a peptide orprotein as defined in feature c1, c2 or c3 of every peptide or proteinentry of Table 1 is preferably a modified nucleic acid sequence, morepreferably as defined herein, which differs in at least one nucleotideresidue from a corresponding naturally occuring nucleic acid sequence.

Preferably, the therapeutic protein encoded by the at least one codingsequence of the RNA is a therapeutic protein as defined herein, which isencoded by a nucleic acid sequence comprising or consisting of any oneof the nucleic acid sequences defined in feature c4 of Table 1, or afragment or variant of any one of these sequences. In other words, thetherapeutic protein encoded by the at least one coding sequence of theRNA is preferably a therapeutic protein as defined herein, which ispreferably encoded by a nucleic acid sequence comprising or consistingof a nucleic acid sequence selected from the group consisting of nucleicacid sequences according to any one of SEQ ID NO: 13058 to 78342, or afragment or variant of any of these sequence.

In a preferred embodiment, the present invention thus provides an RNAcomprising at least one coding sequence, wherein the coding sequencecomprises or consists any one of the nucleic acid sequences defined infeature c4 of Table 1, or a fragment or variant of any one of thesesequences.

In certain embodiments, the RNA according to the invention, preferablythe at least one coding sequence of the RNA according to the invention,may comprise or consist of a fragment of a nucleic acid sequenceencoding a therapeutic protein or a fragment or variant thereof asdefined herein. Preferably, the at least one coding sequence of the RNAaccording to the invention comprises or consists of a fragment,preferably as defined herein, of any one of the nucleic acid sequencesdefined in feature c4 of Table 1, or a fragment or variant of any one ofthese sequences.

In this context, a “fragment of a nucleic acid sequence” is preferably anucleic acid sequence encoding a fragment of a therapeutic protein or ofa variant thereof as described herein. More preferably, the expression“fragment of a nucleic acid sequence” refers to a nucleic acid sequencehaving a sequence identity of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99%, preferably of at least 70%, more preferably of atleast 80%, even more preferably at least 85%, even more preferably of atleast 90% and most preferably of at least 95% or even 97%, with arespective full-length nucleic acid sequence.

In another preferred embodiment, the RNA according to the invention,preferably the at least one coding sequence of the RNA according to theinvention, may comprise or consist of a variant of a nucleic acidsequence as defined herein, preferably of a nucleic acid sequenceencoding a therapeutic protein or a fragment thereof as defined herein.

The expression “variant of a nucleic acid sequence” as used herein inthe context of a nucleic acid sequence encoding a therapeutic protein ora fragment thereof, typically refers to a nucleic acid sequence, whichdiffers by at least one nucleic acid residue from the respectivereference nucleic acid sequence, preferably from the respectivenaturally occuring nucleic acid sequence encoding a therapeutic proteinor a fragment thereof, more preferably from a corresponding nucleic acidsequence specified in Table 1. More preferably, the expression “variantof a nucleic acid sequence” refers to a nucleic acid sequence having asequence identity of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99%, preferably of at least 70%, more preferably of at least80%, even more preferably at least 85%, even more preferably of at least90% and most preferably of at least 95% or even 97%, with a nucleic acidsequence, from which it is derived.

Preferably, the RNA according to the invention, more preferably the atleast one coding sequence of the RNA according to the invention, encodesa variant of a therapeutic protein or a fragment thereof, preferably asdefined herein.

In a preferred embodiment, the RNA according to the invention, morepreferably the at least one coding sequence of the RNA according to theinvention, comprises or consists of a variant of a nucleic acid sequenceencoding a therapeutic protein or a fragment thereof as defined herein,wherein the variant of the nucleic acid sequence encodes an amino acidsequence comprising at least one conservative substitution of an aminoacid residue.

In another embodiment, the RNA according to the invention, morepreferably the at least one coding sequence of the RNA according to theinvention, comprises or consists of a variant of a nucleic acid sequenceencoding a therapeutic protein or a fragment thereof as defined herein,wherein the nucleic acid sequence of the variant differs a referencenucleic acid sequence, preferably from the respective naturally occuringnucleic acid sequence in at least one nucleic acid residue, morepreferably without resulting—due to the degenerated genetic code—in analteration of the encoded amino acid sequence, i.e. the amino acidsequence encoded by the variant or at least part thereof may preferablynot differ from the naturally occuring amino acid sequence in one ormore mutation(s) within the above meaning.

Furthermore, a “variant” of a nucleic acid sequence encoding atherapeutic protein or a fragment or variant thereof as defined herein,may also comprise DNA sequences, which correspond to RNA sequences asdefined herein and may also comprise further RNA sequences, whichcorrespond to DNA sequences as defined herein. Those skilled in the artare familiar with the translation of an RNA sequence into a DNA sequence(or vice versa) or with the creation of the complementary strandsequence (i.e. by substitution of U residues with T residues and/or byconstructing the complementary strand with respect to a given sequence).

According to a preferred embodiment, the at least one coding sequence ofthe RNA according to the invention comprises or consists of a nucleicacid sequence having a sequence identity of at least 5%, 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99%, preferably of at least 70%, morepreferably of at least 80%, even more preferably at least 85%, even morepreferably of at least 90% and most preferably of at least 95% or even97%, with a reference nucleic acid sequence, preferably with a nucleicacid sequence encoding a naturally occuring full-length therapeuticprotein as defined herein, or a variant thereof.

In a further preferred embodiment, the at least one coding sequence ofthe RNA according to the invention comprises or consists of a nucleicacid sequence identical to or having a sequence identity of at least 5%,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably of at least70%, more preferably of at least 80%, even more preferably at least 85%,even more preferably of at least 90% and most preferably of at least 95%or even 97%, with any one of the nucleic acid sequences defined infeature c4 of Table 1, or a fragment or variant thereof. According to aparticularly preferred embodiment, the at least one coding sequence ofthe RNA according to the invention comprises or consists of a nucleicacid sequence having a sequence identity of at least 80% with any one ofthe nucleic acid sequences defined in feature c4 of Table 1, or afragment or variant of any one of these sequences.

In a further preferred embodiment, the at least one coding sequence ofthe RNA according to the invention comprises or consists of a nucleicacid sequence having a sequence identity of at least 5%, 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99%, preferably of at least 70%, morepreferably of at least 80%, even more preferably at least 85%, even morepreferably of at least 90% and most preferably of at least 95% or even97%, with any one of the nucleic acid sequences defined in feature c4 ofTable 1, or a fragment or variant of any one of these sequences. Inother words, the at least one coding sequence of the RNA according tothe invention preferably comprises or consists of a nucleic acidsequence having a sequence identity of at least 5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99%, preferably of at least 70%, more preferablyof at least 80%, even more preferably at least 85%, even more preferablyof at least 90% and most preferably of at least 95% or even 97%, with anucleic acid sequence selected from the group consisting of nucleic acidsequences according to any one of SEQ ID NO: 13058 to 78342, or afragment or variant of any one of said nucleic acid sequences. Accordingto a particularly preferred embodiment, the at least one coding sequenceof the RNA according to the invention comprises or consists of a nucleicacid sequence having a sequence identity of at least 80% with any one ofthe nucleic acid sequences defined in feature c4 of Table 1, or afragment or variant of any one of these sequences.

According to certain embodiments of the present invention, the RNA ismono-, bi-, or multicistronic, preferably as defined herein. The codingsequences in a bi- or multicistronic RNA preferably encode distincttherapeutic protein as defined herein or a fragment or variant thereof.Preferably, the coding sequences encoding two or more peptides orproteins may be separated in the bi- or multicistronic RNA by at leastone IRES (internal ribosomal entry site) sequence, as defined below.Thus, the term “encoding two or more therapeutic proteins” may mean,without being limited thereto, that the bi- or even multicistronic RNA,may encode e.g. at least two, three, four, five, six or more (preferablydifferent) peptides or proteins of the therapeutic proteins or theirfragments or variants within the definitions provided herein. Morepreferably, without being limited thereto, the bi- or evenmulticistronic mRNA, may encode, for example, at least two, three, four,five, six or more (preferably different) therapeutic proteins as definedherein or their fragments or variants as defined herein. In thiscontext, a so-called IRES (internal ribosomal entry site) sequence asdefined above can function as a sole ribosome binding site, but it canalso serve to provide a bi- or even multicistronic mRNA as definedabove, which encodes several therapeutic proteins, which are to betranslated by the ribosomes independently of one another. Examples ofIRES sequences, which can be used according to the invention, are thosefrom picornaviruses (e.g. FMDV), pestiviruses (CFFV), polioviruses (PV),encephalomyocarditis viruses (ECMV), foot and mouth disease viruses(FMDV), hepatitis C viruses (HCV), classical swine fever viruses (CSFV),mouse leukoma virus (MLV), simian immunodeficiency viruses (SIV) orcricket paralysis viruses (CrPV).

According to a further embodiment the at least one coding sequence ofthe RNA according to the invention may encode at least two, three, four,five, six, seven, eight and more therapeutic proteins (or fragments orvariants thereof) as defined herein linked with or without an amino acidlinker sequence, wherein said linker sequence can comprise rigidlinkers, flexible linkers, cleavable linkers (e.g., self-cleavingpeptides) or a combination thereof. Therein, the therapeutic proteins(or fragments or variants thereof) may be identical or different or acombination thereof.

Preferably, the at least one coding sequence of the RNA according to theinvention comprises at least two, three, four, five, six, seven, eightor more nucleic acid sequences identical to or having a sequenceidentity of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%,preferably of at least 70%, more preferably of at least 80%, even morepreferably at least 85%, even more preferably of at least 90% and mostpreferably of at least 95% or even 97%, with any one of the nucleic acidsequences disclosed in feature c4 of Table 1 herein, or a fragment orvariant of any one of said nucleic acid sequences.

Preferably, the RNA comprising at least one coding sequence as definedherein typically comprises a length of about 50 to about 20000, or 100to about 20000 nucleotides, preferably of about 250 to about 20000nucleotides, more preferably of about 500 to about 10000, even morepreferably of about 500 to about 5000.

The RNA according to the invention may further be single stranded ordouble stranded. When provided as a double stranded RNA, the RNAaccording to the invention preferably comprises a sense and acorresponding antisense strand.

In a preferred embodiment, the RNA comprising at least one codingsequence as defined herein is an mRNA, a viral RNA or a replicon RNA.

According to a further embodiment, the RNA, preferably an mRNA,according to the invention is a modified RNA, preferably a modified RNAas described herein. In this context, a modification as defined hereinpreferably leads to a stabilization of the RNA according to theinvention. More preferably, the invention thus provides a stabilized RNAcomprising at least one coding sequence as defined herein.

According to one embodiment, the RNA of the present invention may thusbe provided as a “stabilized mRNA”, that is to say as an RNA that isessentially resistant to in vivo degradation (e.g. by an exo- orendo-nuclease). Such stabilization can be effected, for example, by amodified phosphate backbone of the RNA of the present invention. Abackbone modification in connection with the present invention is amodification, in which phosphates of the backbone of the nucleotidescontained in the RNA are chemically modified. Nucleotides that may bepreferably used in this connection contain e.g. aphosphorothioate-modified phosphate backbone, preferably at least one ofthe phosphate oxygens contained in the phosphate backbone being replacedby a sulfur atom. Stabilized RNAs may further include, for example:non-ionic phosphate analogues, such as, for example, alkyl and arylphosphonates, in which the charged phosphonate oxygen is replaced by analkyl or aryl group, or phosphodiesters and alkylphosphotriesters, inwhich the charged oxygen residue is present in alkylated form. Suchbackbone modifications typically include, without implying anylimitation, modifications from the group consisting ofmethylphosphonates, phosphoramidates and phosphorothioates (e.g.cytidine-5′-0-(1-thiophosphate)).

In the following, specific modifications are described, which arepreferably capable of “stabilizing” the RNA as defined herein.

Chemical Modifications:

The term “RNA modification” as used herein may refer to chemicalmodifications comprising backbone modifications as well as sugarmodifications or base modifications.

In this context, a modified RNA as defined herein may contain nucleotideanalogues/modifications, e.g. backbone modifications, sugarmodifications or base modifications. A backbone modification inconnection with the present invention is a modification, in whichphosphates of the backbone of the nucleotides contained in an RNA asdefined herein are chemically modified. A sugar modification inconnection with the present invention is a chemical modification of thesugar of the nucleotides of the RNA as defined herein. Furthermore, abase modification in connection with the present invention is a chemicalmodification of the base moiety of the nucleotides of the RNA. In thiscontext, nucleotide analogues or modifications are preferably selectedfrom nucleotide analogues, which are applicable for transcription and/ortranslation.

Sugar Modifications:

The modified nucleosides and nucleotides, which may be incorporated intoa modified RNA as described herein, can be modified in the sugar moiety.For example, the 2′ hydroxyl group (OH) can be modified or replaced witha number of different “oxy” or “deoxy” substituents. Examples of“oxy”-2′ hydroxyl group modifications include, but are not limited to,alkoxy or aryloxy (—OR, e.g., R═H, alkyl, cycloalkyl, aryl, aralkyl,heteroaryl or sugar); polyethyleneglycols (PEG),—O(CH₂CH₂O)_(n)CH₂CH₂OR; “locked” nucleic acids (LNA) in which the 2′hydroxyl is connected, e.g., by a methylene bridge, to the 4′ carbon ofthe same ribose sugar; and amino groups (—O-amino, wherein the aminogroup, e.g., NRR, can be alkylamino, dialkylamino, heterocyclyl,arylamino, diarylamino, heteroarylamino, or diheteroaryl amino, ethylenediamine, polyamino) or aminoalkoxy.

“Deoxy” modifications include hydrogen, amino (e.g. NH₂; alkylamino,dialkylamino, heterocyclyl, arylamino, diary) amino, heteroaryl amino,diheteroaryl amino, or amino acid); or the amino group can be attachedto the sugar through a linker, wherein the linker comprises one or moreof the atoms C, N, and D.

The sugar group can also contain one or more carbons that possess theopposite stereochemical configuration than that of the correspondingcarbon in ribose. Thus, a modified RNA can include nucleotidescontaining, for instance, arabinose as the sugar.

Backbone Modifications:

The phosphate backbone may further be modified in the modifiednucleosides and nucleotides, which may be incorporated into a modifiedRNA as described herein. The phosphate groups of the backbone can bemodified by replacing one or more of the oxygen atoms with a differentsubstituent. Further, the modified nucleosides and nucleotides caninclude the full replacement of an unmodified phosphate moiety with amodified phosphate as described herein. Examples of modified phosphategroups include, but are not limited to, phosphorothioate,phosphoroselenates, borano phosphates, borano phosphate esters, hydrogenphosphonates, phosphoroamidates, alkyl or aryl phosphonates andphosphotriesters. Phosphorodithioates have both non-linking oxygensreplaced by sulfur. The phosphate linker can also be modified by thereplacement of a linking oxygen with nitrogen (bridgedphosphoroamidates), sulfur (bridged phosphorothioates) and carbon(bridged methylene-phosphonates).

Base Modifications:

The modified nucleosides and nucleotides, which may be incorporated intoa modified RNA as described herein can further be modified in thenucleobase moiety. Examples of nucleobases found in RNA include, but arenot limited to, adenine, guanine, cytosine and tired. For example, thenucleosides and nucleotides described herein can be chemically modifiedon the major groove face. In some embodiments, the major groove chemicalmodifications can include an amino group, a thiol group, an alkyl group,or a halo group.

In particularly preferred embodiments of the present invention, thenucleotide analogues/modifications are selected from base modifications,which are preferably selected from2-amino-6-chloropurineriboside-5′-triphosphate,2-Aminopurine-riboside-5′-triphosphate;2-aminoadenosine-5′-triphosphate,2′-Amino-2′-deoxycytidine-triphosphate, 2-thiocytidine-5′-triphosphate,2-thiouridine-5′-triphosphate, 2′-Fluorothymidine-5′-triphosphate,2′-0-Methyl-inosine-5′-triphosphate 4-thiouridine-5′-triphosphate,5-aminoallylcytidine-5′-triphosphate,5-aminoallyluridine-5′-triphosphate, 5-bromocytidine-5′-triphosphate,5-bromouridine-5′-triphosphate,5-Bromo-2′-deoxycytidine-5′-triphosphate,5-Bromo-2′-deoxyuridine-5′-triphosphate, 5-iodocytidine-5′-triphosphate,5-lodo-2′-deoxycytidine-5′-triphosphate, 5-iodouridine-5′-triphosphate,5-lodo-2′-deoxyuridine-5′-triphosphate,5-methylcytidine-5′-triphosphate, 5-methyluridine-5′-triphosphate,5-Propynyl-2′-deoxycytidine-5′-triphosphate,5-Propynyl-2′-deoxyuridine-5′-triphosphate,6-azacytidine-5′-triphosphate, 6-azauridine-5′-triphosphate,6-chloropurineriboside-5′-triphosphate, 7-deanadenosine-5′-triphosphate,7-deazaguanosine-5′-triphosphate, 8-azaadenosine-5′-triphosphate,8-azidoadenosine-5′-triphosphate,benzimidazole-riboside-5′-triphosphate,N1-methyladenosine-5′-triphosphate, N1-methylguanosine-5′-triphosphate,N6-methyladenosine-5′-triphosphate, O6-methylguanosine-5′-triphosphate,pseudouridine-5′-triphosphate, or puromycin-5′-triphosphate,xanthosine-5′-triphosphate. Particular preference is given tonucleotides for base modifications selected from the group ofbase-modified nucleotides consisting of5-methylcytidine-5′-triphosphate, 7-deazaguanosine-5′-triphosphate,5-bromocytidine-5′-triphosphate, and pseudouridine-5′-triphosphate.

In some embodiments, modified nucleosides include pyridin-4-oneribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine,4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine,3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine,5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine,1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine,1-taurinomethyl-4-thio-uridine, 5-methyl-uridine,1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine,2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine,2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine,dihydropseudouridine, 2-thio-dihydrouridine,2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine,4-methoxy-pseudouridine, and 4-methoxy-2-thio-pseudouridine.

In some embodiments, modified nucleosides include 5-aza-cytidine,pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine,5-formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine,1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine,2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine,4-thio-1-methyl-pseudoisocytidine,4-thio-1-methyl-1-deaza-pseudoisocytidine,1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine,5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine,2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine,4-methoxy-pseudoisocytidine, and 4-methoxy-1-methyl-pseudoisocytidine.

In other embodiments, modified nucleosides include 2-aminopurine, 2,6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine,7-deaza-2-aminopurine, 7-deaza-8-aza-2-aminopurine,7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine,1-methyladenosine, N6-methyladenosine, N6-isopentenyladenosine,N6-(cis-hydroxyisopentenyCadenosine,2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine,N6-glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine,2-methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine,7-methyladenine, 2-methylthio-adenine, and 2-methoxy-adenine.

In other embodiments, modified nucleosides include inosine,1-methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine,7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine,6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine,6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine,1-methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine,8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine,N2-methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine.

In some embodiments, the nucleotide can be modified on the major grooveface and can include replacing hydrogen on C-5 of uracil with a methylgroup or a halo group. In specific embodiments, a modified nucleoside is5′-0-(1-thiophosphate)-adenosine, 5′-0-(1-thiophosphate)-cytidine,5′-0-(1-thiophosphate)-guanosine, 5′-0-(1-thiophosphate)-uridine or5′-0-(1- thiophosphate)-pseudouridine.

In further specific embodiments, a modified RNA may comprise nucleosidemodifications selected from 6-aza-cytidine, 2-thio-cytidine,α-thio-cytidine, Pseudo-iso-cytidine, 5-aminoallyl-uridine,5-iodo-uridine, N1-methyl-pseudouridine, 5,6-dihydrouridine,α-thio-uridine, 4-thio-uridine, 5-aza-uridine, 5-hydroxy-uridine,deoxy-thymidine, 5-methyl-uridine, Pyrrolo-cytidine, inosine,α-thio-guanosine, 6-methyl-guanosine, 5-methyl-cytdine, 8-oxo-guanosine,7-deaza-guanosine, N1-methyl-adenosine, 2-amino-6-Chloro-purine,N6-methyl-2-amino-purine, Pseudo-iso-cytidine, 6-Chloro-purine,N6-methyl-adenosine, α-thio-adenosine, 8-azido-adenosine,7-deaza-adenosine.

Lipid Modification:

According to a further embodiment, a modified RNA as defined herein cancontain a lipid modification. Such a lipid-modified RNA typicallycomprises an RNA as defined herein. Such a lipid-modified RNA as definedherein typically further comprises at least one linker covalently linkedwith that RNA, and at least one lipid covalently linked with therespective linker. Alternatively, the lipid-modified RNA comprises atleast one RNA as defined herein and at least one (bifunctional) lipidcovalently linked (without a linker) with that RNA. According to a thirdalternative, the lipid-modified RNA comprises an RNA molecule as definedherein, at least one linker covalently linked with that RNA, and atleast one lipid covalently linked with the respective linker, and alsoat least one (bifunctional) lipid covalently linked (without a linker)with that RNA. In this context, it is particularly preferred that thelipid modification is present at the terminal ends of a linear RNAsequence.

G/C Content Modification:

According to another embodiment, the RNA of the present invention,preferably an mRNA, may be modified, and thus stabilized, by modifyingthe guanosine/cytosine (G/C) content of the RNA, preferably of the atleast one coding sequence of the RNA of the present invention.

In a particularly preferred embodiment of the present invention, the G/Ccontent of the coding sequence (coding region) of the RNA of the presentinvention is modified, particularly increased, compared to the G/Ccontent of the coding region of the respective wild type RNA, i.e. theunmodified RNA. The amino acid sequence encoded by the RNA is preferablynot modified as compared to the amino acid sequence encoded by therespective wild type RNA. This modification of the RNA of the presentinvention is based on the fact that the sequence of any RNA region to betranslated is important for efficient translation of that RNA. Thus, thecomposition of the RNA and the sequence of various nucleotides areimportant. In particular, sequences having an increased G (guanosine)/C(cytosine) content are more stable than sequences having an increased A(adenosine)/U (uracil) content. According to the invention, the codonsof the RNA are therefore varied compared to the respective wild typeRNA, while retaining the translated amino acid sequence, such that theyinclude an increased amount of G/C nucleotides. In respect to the factthat several codons code for one and the same amino acid (so-calleddegeneration of the genetic code), the most favourable codons for thestability can be determined (so-called alternative codon usage).Depending on the amino acid to be encoded by the RNA, there are variouspossibilities for modification of the RNA sequence, compared to its wildtype sequence. In the case of amino acids, which are encoded by codons,which contain exclusively G or C nucleotides, no modification of thecodon is necessary. Thus, the codons for Pro (CCC or CCG), Arg (CGC orCGG), Ala (GCC or GCG) and Gly (GGC or GGG) require no modification,since no A or U is present. In contrast, codons which contain A and/or Unucleotides can be modified by substitution of other codons, which codefor the same amino acids but contain no A and/or U. Examples of theseare: the codons for Pro can be modified from CCU or CCA to CCC or CCG;the codons for Arg can be modified from CGU or CGA or AGA or AGG to CGCor CGG; the codons for Ala can be modified from GCU or GCA to GCC orGCG; the codons for Gly can be modified from GGU or GGA to GGC or GGG.In other cases, although A or U nucleotides cannot be eliminated fromthe codons, it is however possible to decrease the A and U content byusing codons which contain a lower content of A and/or U nucleotides.Examples of these are: the codons for Phe can be modified from UUU toUUC; the codons for Leu can be modified from UUA, UUG, CUU or CUA to CUCor CUG; the codons for Ser can be modified from UCU or UCA or AGU toUCC, UCG or AGC; the codon for Tyr can be modified from UAU to UAC; thecodon for Cys can be modified from UGU to UGC; the codon for His can bemodified from CAU to CAC; the codon for Gln can be modified from CAA toCAG; the codons for Ile can be modified from AUU or AUA to AUC; thecodons for Thr can be modified from ACU or ACA to ACC or ACG; the codonfor Asn can be modified from AAU to AAC; the codon for Lys can bemodified from AAA to AAG; the codons for Val can be modified from GUU orGUA to GUC or GUG; the codon for Asp can be modified from GAU to GAC;the codon for Glu can be modified from GAA to GAG; the stop codon UAAcan be modified to UAG or UGA. In the case of the codons for Met (AUG)and Trp (UGG), on the other hand, there is no possibility of sequencemodification. The substitutions listed above can be used eitherindividually or in all possible combinations to increase the G/C contentof the at least one mRNA of the composition of the present inventioncompared to its particular wild type mRNA (i.e. the original sequence).Thus, for example, all codons for Thr occurring in the wild typesequence can be modified to ACC (or ACG). Preferably, however, forexample, combinations of the above substitution possibilities are used:

substitution of all codons coding for Thr in the original sequence (wildtype mRNA) to ACC (or ACG) and

substitution of all codons originally coding for Ser to UCC (or UCG orAGC); substitution of all codons coding for Ile in the original sequenceto AUC and

substitution of all codons originally coding for Lys to AAG and

substitution of all codons originally coding for Tyr to UAC;substitution of all codons coding for Val in the original sequence toGUC (or GUG) and

substitution of all codons originally coding for Glu to GAG and

substitution of all codons originally coding for Ala to GCC (or GCG) and

substitution of all codons originally coding for Arg to CGC (or CGG);substitution of all codons coding for Val in the original sequence toGUC (or GUG) and

substitution of all codons originally coding for Glu to GAG and

substitution of all codons originally coding for Ala to GCC (or GCG) and

substitution of all codons originally coding for Gly to GGC (or GGG) and

substitution of all codons originally coding for Asn to AAC;substitution of all codons coding for Val in the original sequence toGUC (or GUG) and

substitution of all codons originally coding for Phe to UUC and

substitution of all codons originally coding for Cys to UGC and

substitution of all codons originally coding for Leu to CUG (or CUC) and

substitution of all codons originally coding for Gln to CAG and

substitution of all codons originally coding for Pro to CCC (or CCG);etc.

Preferably, the G/C content of the coding region of the RNA of thepresent invention is increased by at least 7%, more preferably by atleast 15%, particularly preferably by at least 20%, compared to the G/Ccontent of the coding region of the wild type RNA, which codes for atherapeutic protein as defined herein or a fragment or variant thereof.According to a specific embodiment at least 5%, 10%, 20%, 30%, 40%, 50%,60%, more preferably at least 70%, even more preferably at least 80% andmost preferably at least 90%, 95% or even 100% of the substitutablecodons in the region coding for a therapeutic protein as defined hereinor a fragment or variant thereof or the whole sequence of the wild typeRNA sequence are substituted, thereby increasing the GC/content of saidsequence. In this context, it is particularly preferable to increase theG/C content of the RNA of the present invention, preferably of the atleast one coding region of the RNA according to the invention, to themaximum (i.e. 100% of the substitutable codons) as compared to the wildtype sequence. According to the invention, a further preferredmodification of the RNA of the present invention is based on the findingthat the translation efficiency is also determined by a differentfrequency in the occurrence of tRNAs in cells. Thus, if so-called “rarecodons” are present in the RNA of the present invention to an increasedextent, the corresponding modified RNA sequence is translated to asignificantly poorer degree than in the case where codons coding forrelatively “frequent” tRNAs are present. According to the invention, inthe modified RNA of the present invention, the region which codes for atherapeutic protein as defined herein or a fragment or variant thereofis modified compared to the corresponding region of the wild type RNAsuch that at least one codon of the wild type sequence, which codes fora tRNA which is relatively rare in the cell, is exchanged for a codon,which codes for a tRNA which is relatively frequent in the cell andcarries the same amino acid as the relatively rare tRNA. By thismodification, the sequences of the RNA of the present invention ismodified such that codons for which frequently occurring tRNAs areavailable are inserted. In other words, according to the invention, bythis modification all codons of the wild type sequence, which code for atRNA which is relatively rare in the cell, can in each case be exchangedfor a codon, which codes for a tRNA which is relatively frequent in thecell and which, in each case, carries the same amino acid as therelatively rare tRNA. Which tRNAs occur relatively frequently in thecell and which, in contrast, occur relatively rarely is known to aperson skilled in the art; cf. e.g. Akashi, Curr. Dpin. Genet. Dev.2001, 11(6): 660-666. The codons, which use for the particular aminoacid the tRNA which occurs the most frequently, e.g. the Gly codon,which uses the tRNA, which occurs the most frequently in the (human)cell, are particularly preferred. According to the invention, it isparticularly preferable to link the sequential G/C content which isincreased, in particular maximized, in the modified RNA of the presentinvention, with the “frequent” codons without modifying the amino acidsequence of the protein encoded by the coding region of the RNA. Thispreferred embodiment allows provision of a particularly efficientlytranslated and stabilized (modified) RNA of the present invention. Thedetermination of a modified RNA of the present invention as describedabove (increased G/C content; exchange of tRNAs) can be carried outusing the computer program explained in WO 02/098443—the disclosurecontent of which is included in its full scope in the present invention.Using this computer program, the nucleotide sequence of any desired RNAcan be modified with the aid of the genetic code or the degenerativenature thereof such that a maximum G/C content results, in combinationwith the use of codons which code for tRNAs occurring as frequently aspossible in the cell, the amino acid sequence coded by the modified RNApreferably not being modified compared to the non-modified sequence.Alternatively, it is also possible to modify only the G/C content oronly the codon usage compared to the original sequence. The source codein Visual Basic 6.0 (development environment used: Microsoft VisualStudio Enterprise 6.0 with Servicepack 3) is also described in WO02/098443. In a further preferred embodiment of the present invention,the A/U content in the environment of the ribosome binding site of theRNA of the present invention is increased compared to the A/U content inthe environment of the ribosome binding site of its respective wild typemRNA. This modification (an increased A/U content around the ribosomebinding site) increases the efficiency of ribosome binding to the RNA.An effective binding of the ribosomes to the ribosome binding site(Kozak sequence: SEQ ID NO: 801; the AUG forms the start codon) in turnhas the effect of an efficient translation of the RNA. According to afurther embodiment of the present invention, the RNA of the presentinvention may be modified with respect to potentially destabilizingsequence elements. Particularly, the coding region and/or the 5′ and/or3′ untranslated region of this RNA may be modified compared to therespective wild type RNA such that it contains no destabilizing sequenceelements, the encoded amino acid sequence of the modified RNA preferablynot being modified compared to its respective wild type RNA. It is knownthat, for example in sequences of eukaryotic RNAs, destabilizingsequence elements (DSE) occur, to which signal proteins bind andregulate enzymatic degradation of RNA in vivo. For further stabilizationof the modified RNA, optionally in the region which encodes atherapeutic protein as defined herein or a fragment or variant thereof,one or more such modifications compared to the corresponding region ofthe wild type RNA can therefore be carried out, so that no orsubstantially no destabilizing sequence elements are contained there.According to the invention, DSE present in the untranslated regions (3′-and/or 5′-UTR) can also be eliminated from the RNA of the presentinvention by such modifications. Such destabilizing sequences are e.g.AU-rich sequences (AURES), which occur in 3′-UTR sections of numerousunstable RNAs (Caput et al., Proc. Natl. Acad. Sci. USA 1986, 83: 1670to 1674). The RNA of the present invention is therefore preferablymodified compared to the respective wild type RNA such that the RNA ofthe present invention contains no such destabilizing sequences. Thisalso applies to those sequence motifs which are recognized by possibleendonucleases, e.g. the sequence GAACAAG, which is contained in the3′-UTR segment of the gene encoding the transferrin receptor (Binder etal., EMBO J. 1994, 13: 1969 to 1980). These sequence motifs are alsopreferably removed in the RNA of the present invention.

According to a preferred embodiment, the present invention provides anRNA as defined herein comprising at least one coding sequence, whereinthe coding sequence comprises or consists of any one of the (modified)nucleic acid sequences defined in feature c4 of Table 1, or of afragment or variant of any one of these sequences. In other words, theat least one coding sequence preferably comprises or consists of anucleic acid sequence selected from the group consisting of nucleic acidsequences according to any one of SEQ ID NO: 13058 to 78342, or afragment or variant of any one of these nucleic acid sequences.

In a further preferred embodiment, the at least one coding sequence ofthe RNA according to the invention comprises or consists of a nucleicacid sequence identical to or having a sequence identity of at least 5%,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably of at least70%, more preferably of at least 80%, even more preferably at least 85%,even more preferably of at least 90% and most preferably of at least 95%or even 97%, with any one of the (modified) nucleic acid sequencesdefined in feature c4 of Table 1, or of a fragment or variant of any oneof these sequences.

According to a particularly preferred embodiment, the at least onecoding sequence of the RNA according to the invention comprises orconsists of a nucleic acid sequence having a sequence identity of atleast 80% with any one of the (modified) nucleic acid sequences definedin feature c4 of Table 1, or of a fragment or variant of any one ofthese sequences.

GC-optimized Sequences:

In a preferred embodiment, the present invention provides an RNAcomprising at least one coding sequence, wherein the coding sequencecomprises or consists of a nucleic acid sequence selected from the groupconsisting of nucleic acid sequences according to any one of SEQ ID NO:26115 to 39171 or SEQ ID NO: 65286 to 78342, or a fragment or variant ofany one of these nucleic acid sequences.

According to a further embodiment, the at least one coding sequence ofthe RNA according to the invention comprises or consists of a nucleicacid sequence having a sequence identity of at least 5%, 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99%, preferably of at least 70%, morepreferably of at least 80%, even more preferably at least 85%, even morepreferably of at least 90% and most preferably of at least 95% or even97%, with a nucleic acid sequence selected from the group consisting ofnucleic acid sequences according to any one of SEQ ID NO: 26115 to 39171or SEQ ID NO: 65286 to 78342, or a fragment or variant of any one ofthese nucleic acid sequences.

Sequences Adapted to Human Codon Usage:

According to the invention, a further preferred modification of the RNAof the present invention is based on the finding that codons encodingthe same amino acid typically occur at different frequencies. Accordingto the invention, in the modified RNA of the present invention, thecoding sequence (coding region) as defined herein is preferably modifiedcompared to the corresponding region of the respective wild type RNAsuch that the frequency of the codons encoding the same amino acidcorresponds to the naturally occurring frequency of that codon accordingto the human codon usage as e.g. shown in Table B.

For example, in the case of the amino acid alanine (Ala) present in anamino acid sequence encoded by the at least one coding sequence of theRNA according to the invention, the wild type coding sequence ispreferably adapted in a way that the codon “GCC” is used with afrequency of 0.40, the codon “GCT” is used with a frequency of 0.28, thecodon “GCA” is used with a frequency of 0.22 and the codon “GCG” is usedwith a frequency of 0.10 etc. (see Table B).

TABLE B Human codon usage table Amino acid codon fraction /1000 Ala GCG0.10  7.4 Ala GCA 0.22 15.8 Ala GCT 0.28 18.5 Ala GCC* 0.40 27.7 Cys TGT0.42 10.6 Cys TGC* 0.58 12.6 Asp GAT 0.44 21.8 Asp GAC* 0.56 25.1 GluGAG* 0.59 39.6 Glu GAA 0.41 29.0 Phe TTT 0.43 17.6 Phe TTC* 0.57 20.3Gly GGG 0.23 16.5 Gly GGA 0.26 16.5 Gly GGT 0.18 10.8 Gly GGC* 0.33 22.2His CAT 0.41 10.9 His CAC* 0.59 15.1 Ile ATA 0.14  7.5 Ile ATT 0.35 16.0Ile ATC* 0.52 20.8 Lys AAG* 0.60 31.9 Lys AAA 0.40 24.4 Leu TTG 0.1212.9 Leu TTA 0.06  7.7 Leu CTG* 0.43 39.6 Leu CTA 0.07  7.2 Leu CTT 0.1213.2 Leu CTC 0.20 19.6 Met ATG* 1 22.0 Asn AAT 0.44 17.0 Asn AAC* 0.5619.1 Pro CCG 0.11  6.9 Pro CCA 0.27 16.9 Pro CCT 0.29 17.5 Pro CCC* 0.3319.8 Gln CAG* 0.73 34.2 Gln CAA 0.27 12.3 Arg AGG 0.22 12.0 Arg AGA*0.21 12.1 Arg CGG 0.19 11.4 Arg CGA 0.10  6.2 Arg CGT 0.09  4.5 Arg CGC0.19 10.4 Ser AGT 0.14 12.1 Ser AGC* 0.25 19.5 Ser TCG 0.06  4.4 Ser TCA0.15 12.2 Ser TCT 0.18 15.2 Ser TCC 0.23 17.7 Thr ACG 0.12  6.1 Thr ACA0.27 15.1 Thr ACT 0.23 13.1 Thr ACC* 0.38 18.9 Val GTG* 0.48 28.1 ValGTA 0.10  7.1 Val GTT 0.17 11.0 Val GTC 0.25 14.5 Trp TGG* 1 13.2 TyrTAT 0.42 12.2 Tyr TAC* 0.58 15.3 Stop TGA* 0.61  1.6 Stop TAG 0.17  0.8Stop TAA 0.22  1.0 *most frequent codon

In a preferred embodiment, the present invention provides an RNAcomprising at least one coding sequence, wherein the coding sequencecomprises a nucleic acid sequence selected from the group consisting ofnucleic acid sequences according to any one of SEQ ID NO: 52229 to65285, or a fragment or variant of any one of said nucleic acidsequences.

According to a further embodiment, the at least one coding sequence ofthe RNA according to the invention comprises or consists of a nucleicacid sequence having a sequence identity of at least 5%, 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99%, preferably of at least 70%, morepreferably of at least 80%, even more preferably at least 85%, even morepreferably of at least 90% and most preferably of at least 95% or even97%, with a nucleic acid sequence selected from the group consisting ofnucleic acid sequences according to any one of SEQ ID NO: 52229 to65285, or a fragment or variant of any one of said nucleic acidsequences.

Codon-optimized Sequences:

As described above it is preferred according to the invention, that allcodons of the wild type sequence which code for a tRNA, which isrelatively rare in the cell, are exchanged for a codon which codes for atRNA, which is relatively frequent in the cell and which, in each case,carries the same amino acid as the relatively rare tRNA. Therefore it isparticularly preferred that the most frequent codons are used for eachencoded amino acid (see Table B, most frequent codons are marked withasterisks). Such an optimization procedure increases the codonadaptation index (CAI) and ultimately maximises the CAI. In the contextof the invention, sequences with increased or maximized CAI aretypically referred to as “codon-optimized” sequences and/or CAIincreased and/or maximized sequences. According to a preferredembodiment, the RNA of the present invention comprises at least onecoding sequence, wherein the coding sequence is codon-optimized asdescribed herein. More preferably, the codon adaptation index (CAI) ofthe at least one coding sequence is at least 0.5, at least 0.8, at least0.9 or at least 0.95. Most preferably, the codon adaptation index (CAI)of the at least one coding sequence is 1.

For example, in the case of the amino acid alanine (Ala) present in theamino acid sequence encoded by the at least one coding sequence of theRNA according to the invention, the wild type coding sequence is adaptedin a way that the most frequent human codon “GCC” is always used forsaid amino acid, or for the amino acid Cysteine (Cys), the wild typesequence is adapted in a way that the most frequent human codon “TGC” isalways used for said amino acid etc.

In a preferred embodiment, the present invention provides an RNAcomprising at least one coding sequence, wherein the coding sequencecomprises a nucleic acid sequence selected from the group consisting ofnucleic acid sequences according to any one of SEQ ID NO: 13058 to26114, or a fragment or variant of any one of said nucleic acidsequences.

According to a further embodiment, the at least one coding sequence ofthe RNA according to the invention comprises or consists of a nucleicacid sequence having a sequence identity of at least 5%, 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99%, preferably of at least 70%, morepreferably of at least 80%, even more preferably at least 85%, even morepreferably of at least 90% and most preferably of at least 95% or even97%, with a nucleic acid sequence selected from the group consisting ofnucleic acid sequences according to any one of SEQ ID NO: 13058 to26114, or a fragment or variant of any one of said nucleic acidsequences.

C-optimized Sequences:

According to another embodiment, the RNA of the composition of thepresent invention may be modified by modifying, preferably increasing,the cytosine (C) content of the RNA, preferably of the coding region ofthe sRNA.

In a particularly preferred embodiment of the present invention, the Ccontent of the coding region of the RNA of the present invention ismodified, preferably increased, compared to the C content of the codingregion of the respective wild type RNA, i.e. the unmodified RNA. Theamino acid sequence encoded by the at least one coding sequence of theRNA of the present invention is preferably not modified as compared tothe amino acid sequence encoded by the respective wild type mRNA.

In a preferred embodiment of the present invention, the modified RNA ismodified such that at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, orat least 90% of the theoretically possible maximum cytosine-content oreven a maximum cytosine-content is achieved.

In further preferred embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90% or even 100% of the codons of the target RNA wild typesequence, which are “cytosine content optimizable” are replaced bycodons having a higher cytosine-content than the ones present in thewild type sequence.

In a further preferred embodiment, some of the codons of the wild typecoding sequence may additionally be modified such that a codon for arelatively rare tRNA in the cell is exchanged by a codon for arelatively frequent tRNA in the cell, provided that the substitutedcodon for a relatively frequent tRNA carries the same amino acid as therelatively rare tRNA of the original wild type codon. Preferably, all ofthe codons for a relatively rare tRNA are replaced by a codon for arelatively frequent tRNA in the cell, except codons encoding aminoacids, which are exclusively encoded by codons not containing anycytosine, or except for glutamine (Gln), which is encoded by two codonseach containing the same number of cytosines.

In a further preferred embodiment of the present invention, the modifiedtarget RNA is modified such that at least 80%, or at least 90% of thetheoretically possible maximum cytosine-content or even a maximumcytosine-content is achieved by means of codons, which code forrelatively frequent tRNAs in the cell, wherein the amino acid sequenceremains unchanged.

Due to the naturally occurring degeneracy of the genetic code, more thanone codon may encode a particular amino acid. Accordingly, 18 out of 20naturally occurring amino acids are encoded by more than one codon (withTryp and Met being an exception), e.g. by 2 codons (e.g. Cys, Asp, Glu),by three codons (e.g. Ile), by 4 codons (e.g. Al, Gly, Pro) or by 6codons (e.g. Leu, Arg, Ser). However, not all codons encoding the sameamino acid are utilized with the same frequency under in vivoconditions. Depending on each single organism, a typical codon usageprofile is established.

The term “cytosine content-optimizable codon” as used within the contextof the present invention refers to codons, which exhibit a lower contentof cytosines than other codons encoding the same amino acid.Accordingly, any wild type codon, which may be replaced by another codonencoding the same amino acid and exhibiting a higher number of cytosineswithin that codon, is considered to be cytosine-optimizable(C-optimizable). Any such substitution of a C-optimizable wild typecodon by the specific C-optimized codon within a wild type coding regionincreases its overall C-content and reflects a C-enriched modified mRNAsequence. According to a preferred embodiment, the RNA of the presentinvention, preferably the at least one coding sequence of the RNA of thepresent invention comprises or consists of a C-maximized RNA sequencecontaining C-optimized codons for all potentially C-optimizable codons.Accordingly, 100% or all of the theoretically replaceable C-optimizablecodons are preferably replaced by C-optimized codons over the entirelength of the coding region.

In this context, cytosine-content optimizable codons are codons, whichcontain a lower number of cytosines than other codons coding for thesame amino acid.

Any of the codons GCG, GCA, GCU codes for the amino acid Ala, which maybe exchanged by the codon GCC encoding the same amino acid, and/or

the codon UGU that codes for Cys may be exchanged by the codon UGCencoding the same amino acid, and/or

the codon GAU which codes for Asp may be exchanged by the codon GACencoding the same amino acid, and/or

the codon that UUU that codes for Phe may be exchanged for the codon UUCencoding the same amino acid, and/or

any of the codons GGG, GGA, GGU that code Gly may be exchanged by thecodon GGC encoding the same amino acid, and/or

the codon CAU that codes for His may be exchanged by the codon CACencoding the same amino acid, and/or

any of the codons AUA, AUU that code for Ile may be exchanged by thecodon AUC, and/or

any of the codons UUG, UUA, CUG, CUA, CUU coding for Leu may beexchanged by the codon CUC encoding the same amino acid, and/or

the codon AAU that codes for Asn may be exchanged by the codon AACencoding the same amino acid, and/or

any of the codons CCG, CCA, CCU coding for Pro may be exchanged by thecodon CCC encoding the same amino acid, and/or

any of the codons AGG, AGA, CGG, CGA, CGU coding for Arg may beexchanged by the codon CGC encoding the same amino acid, and/or

any of the codons AGU, AGC, UCG, UCA, UCU coding for Ser may beexchanged by the codon UCC encoding the same amino acid, and/or

any of the codons ACG, ACA, ACU coding for Thr may be exchanged by thecodon ACC encoding the same amino acid, and/or

any of the codons GUG, GUA, GUU coding for Val may be exchanged by thecodon GUC encoding the same amino acid, and/or

the codon UAU coding for Tyr may be exchanged by the codon UAC encodingthe same amino acid.

In any of the above instances, the number of cytosines is increased by 1per exchanged codon. Exchange of all non C-optimized codons(corresponding to C-optimizable codons) of the coding region results ina C-maximized coding sequence. In the context of the invention, at least70%, preferably at least 80%, more preferably at least 90%, of the nonC-optimized codons within the at least one coding region of the RNAaccording to the invention are replaced by C-optimized codons.

It may be preferred that for some amino acids the percentage ofC-optimizable codons replaced by C-optimized codons is less than 70%,while for other amino acids the percentage of replaced codons is higherthan 70% to meet the overall percentage of C-optimization of at least70% of all C-optimizable wild type codons of the coding region.

Preferably, in a C-optimized RNA of the invention, at least 50% of theC-optimizable wild type codons for any given amino acid are replaced byC-optimized codons, e.g. any modified C-enriched RNA preferably containsat least 50% C-optimized codons at C-optimizable wild type codonpositions encoding any one of the above mentioned amino acids Ala, Cys,Asp, Phe, Gly, His, Ile, Leu, Asn, Pro, Arg, Ser, Thr, Val and Tyr,preferably at least 60%.

In this context codons encoding amino acids, which are not cytosinecontent-optimizable and which are, however, encoded by at least twocodons, may be used without any further selection process. However, thecodon of the wild type sequence that codes for a relatively rare tRNA inthe cell, e.g. a human cell, may be exchanged for a codon that codes fora relatively frequent tRNA in the cell, wherein both code for the sameamino acid. Accordingly, the relatively rare codon GAA coding for Glumay be exchanged by the relative frequent codon GAG coding for the sameamino acid, and/or

the relatively rare codon AAA coding for Lys may be exchanged by therelative frequent codon AAG coding for the same amino acid, and/or

the relatively rare codon CAA coding for Gln may be exchanged for therelative frequent codon CAG encoding the same amino acid.

In this context, the amino acids Met (AUG) and Trp (UGG), which areencoded by only one codon each, remain unchanged. Stop codons are notcytosine-content optimized, however, the relatively rare stop codonsamber, ochre (UAA, UAG) may be exchanged by the relatively frequent stopcodon opal (USA).

The single substitutions listed above may be used individually as wellas in all possible combinations in order to optimize thecytosine-content of the modified RNA compared to the wild type mRNAsequence.

Accordingly, the at least one coding sequence as defined herein may bechanged compared to the coding region of the respective wild type RNA insuch a way that an amino acid encoded by at least two or more codons, ofwhich one comprises one additional cytosine, such a codon may beexchanged by the C-optimized codon comprising one additional cytosine,wherein the amino acid is preferably unaltered compared to the wild typesequence.

In a preferred embodiment, the present invention provides an RNAcomprising at least one coding sequence, wherein the coding sequencecomprises a nucleic acid sequence selected from the group consisting ofnucleic acid sequences according to any one of SEQ ID NO: 39172 to52228, or a fragment or variant of any one of said nucleic acidsequences.

According to a further embodiment, the at least one coding sequence ofthe RNA according to the invention comprises or consists of a nucleicacid sequence having a sequence identity of at least 5%, 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99%, preferably of at least 70%, morepreferably of at least 80%, even more preferably at least 85%, even morepreferably of at least 90% and most preferably of at least 95% or even97%, with a nucleic acid sequence selected from the group consisting ofnucleic acid sequences according to any one of SEQ ID NO: 39172 to52228, or a fragment or variant of any one of said nucleic acidsequences.

According to a particularly preferred embodiment, the invention providesan RNA, preferably an mRNA, comprising at least one coding sequence asdefined herein, wherein the G/C content of the at least one codingsequence of the RNA is increased compared to the G/C content of thecorresponding coding sequence of the corresponding wild type RNA, and/or

wherein the C content of the at least one coding sequence of the RNA isincreased compared to the C content of the corresponding coding sequenceof the corresponding wild type RNA, and/or

wherein the codons in the at least one coding sequence of the RNA areadapted to human codon usage, wherein the codon adaptation index (CAI)is preferably increased or maximised in the at least one coding sequenceof the RNA,

and wherein the amino acid sequence encoded by the RNA is preferably notbeing modified compared to the amino acid sequence encoded by thecorresponding wild type RNA.

According to another preferred embodiment of the invention, a modifiedRNA as defined herein, can be modified by the addition of a so-called“5′ cap” structure, which preferably stabilizes the RNA as describedherein. A 5′-cap is an entity, typically a modified nucleotide entity,which generally “caps” the 5′-end of a mature mRNA. A 5′-cap maytypically be formed by a modified nucleotide, particularly by aderivative of a guanine nucleotide. Preferably, the 5′-cap is linked tothe 5′-terminus via a 5′-5′-triphosphate linkage. A 5′-cap may bemethylated, e.g. m7GpppN, wherein N is the terminal 5′ nucleotide of thenucleic acid carrying the 5′-cap, typically the 5′-end of an mRNA.m7GpppN is the 5′-cap structure, which naturally occurs in mRNAtranscribed by polymerase II and is therefore preferably not consideredas modification comprised in a modified mRNA in this context.Accordingly, a modified RNA of the present invention may comprise am7GpppN as 5′-cap, but additionally the modified RNA typically comprisesat least one further modification as defined herein.

Further examples of 5′-cap structures include glyceryl, inverted deoxyabasic residue (moiety), 4′,5′ methylene nucleotide,1-(beth-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide, carbocyclicnucleotide, 1,5-anhydrohexitol nucleotide, L-nucleotides,alpha-nucleotide, modified base nucleotide, threo-pentofuranosylnucleotide, acyclic 3′,4′-seco nucleotide, acyclic 3,4-dihydroxybutylnucleotide, acyclic 3,5 dihydroxypentyl nucleotide, 3′-3′-invertednucleotide moiety, 3′-3′-inverted abasic moiety, 3′-2′-invertednucleotide moiety, 3′-2′-inverted abasic moiety, 1,4-butanediolphosphate, 3′-phosphoramidate, hexylphosphate, aminohexyl phosphate,3′-phosphate, 3′ phosphorothioate, phosphorodithioate, or bridging ornon-bridging methylphosphonate moiety. These modified 5′-cap structuresare regarded as at least one modification in this context.

Particularly preferred modified 5′-cap structures are cap1 (methylationof the ribose of the adjacent nucleotide of m7G), cap2 (additionalmethylation of the ribose of the 2nd nucleotide downstream of the m7G),cap3 (additional methylation of the ribose of the 3rd nucleotidedownstream of the m7G), cap4 (methylation of the ribose of the 4thnucleotide downstream of the m7G), AREA (anti-reverse cap analogue,modified ARCA (e.g. phosphothioate modified ARCA), inosine,N1-methyl-guanosine, 2′-fluoro-guanosine, 7-deaza-guanosine,8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and2-azido-guanosine. Accordingly, the RNA according to the inventionpreferably comprises a 5′-cap structure.

In a preferred embodiment, the RNA according to the invention comprisesat least one 5′- or 3′-UTR element. In this context, an UTR elementcomprises or consists of a nucleic acid sequence, which is derived fromthe 5′- or 3′-UTR of any naturally occurring gene or which is derivedfrom a fragment, a homolog or a variant of the 5′- or 3′-UTR of a gene.Preferably, the 5′- or 3′-UTR element used according to the presentinvention is heterologous to the at least one coding sequence of the RNAof the invention. Even if 5′- or 3′-UTR elements derived from naturallyoccurring genes are preferred, also synthetically engineered UTRelements may be used in the context of the present invention.

The term “3′-UTR element” typically refers to a nucleic acid sequence,which comprises or consists of a nucleic acid sequence that is derivedfrom a 3′-UTR or from a variant of a 3′-UTR. A 3′-UTR element in thesense of the present invention may represent the 3′-UTR of an RNA,preferably an mRNA. Thus, in the sense of the present invention,preferably, a 3′-UTR element may be the 3′-UTR of an RNA, preferably ofan mRNA, or it may be the transcription template for a 3′-UTR of an RNA.Thus, a 3′-UTR element preferably is a nucleic acid sequence whichcorresponds to the 3′-UTR of an RNA, preferably to the 3′-UTR of anmRNA, such as an mRNA obtained by transcription of a geneticallyengineered vector construct. Preferably, the 3′-UTR element fulfils thefunction of a 3′-UTR or encodes a sequence which fulfils the function ofa 3′-UTR.

According to a preferred embodiment, the RNA, preferably an mRNA,according to the invention comprises a 5′-cap structure and/or at leastone 3′-untranslated region element (3′-UTR element), preferably asdefined herein. More preferably, the RNA further comprises a 5′-UTRelement as defined herein.

According to a further preferred embodiment, the RNA of the presentinvention may contain a poly-A tail on the 3′ terminus of typicallyabout 10 to 200 adenosine nucleotides, preferably about 10 to 100adenosine nucleotides, more preferably about 40 to 80 adenosinenucleotides or even more preferably about 50 to 70 adenosinenucleotides.

Preferably, the poly(A) sequence in the RNA of the present invention isderived from a DNA template by RNA in vitro transcription.Alternatively, the poly(A) sequence may also be obtained in vitro bycommon methods of chemical-synthesis without being necessarilytranscribed from a DNA-progenitor. Moreover, poly(A) sequences, orpoly(A) tails may be generated by enzymatic polyadenylation of the RNAaccording to the present invention using commercially availablepolyadenylation kits and corresponding protocols known in the art.

Alternatively, the RNA as described herein optionally comprises apolyadenylation signal, which is defined herein as a signal, whichconveys polyadenylation to a (transcribed) RNA by specific proteinfactors (e.g. cleavage and polyadenylation specificity factor (CPSF),cleavage stimulation factor (CstF), cleavage factors I and II (CF I andCF II), poly(A) polymerase (PAP)). In this context, a consensuspolyadenylation signal is preferred comprising the NN(U/T)ANA consensussequence. In a particularly preferred aspect, the polyadenylation signalcomprises one of the following sequences: AA(U/T)AAA or A(U/T)(U/T)AAA(wherein uridine is usually present in RNA and thymidine is usuallypresent in DNA).

According to a further preferred embodiment, the RNA of the presentinvention may contain a poly(C) tail on the 3′ terminus of typicallyabout 10 to 200 cytosine nucleotides, preferably about ID to IDDcytosine nucleotides, more preferably about 20 to 70 cytosinenucleotides or even more preferably about 20 to 60 or even 10 to 40cytosine nucleotides.

In a further preferred embodiment, the RNA according to the inventionfurther comprises at least one 3′-UTR element. Preferably, the at leastone 3′-UTR element comprises or consists of a nucleic acid sequencederived from the 3′-UTR of a chordate gene, preferably a vertebrategene, more preferably a mammalian gene, most preferably a human gene, orfrom a variant of the 3′-UTR of a chordate gene, preferably a vertebrategene, more preferably a mammalian gene, most preferably a human gene.

Preferably, the RNA of the present invention comprises a 3′-UTR element,which may be derivable from a gene that relates to an mRNA with anenhanced half-life (that provides a stable mRNA), for example a 3′-UTRelement as defined and described below. Preferably, the 3′-UTR elementis a nucleic acid sequence derived from a 3′-UTR of a gene, whichpreferably encodes a stable mRNA, or from a homolog, a fragment or avariant of said gene

In a particularly preferred embodiment, the 3′-UTR element comprises orconsists of a nucleic acid sequence, which is derived from a 3′-UTR of agene selected from the group consisting of an albumin gene, an α-globingene, a β-globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene,and a collagen alpha gene, such as a collagen alpha 1(I) gene, or from avariant of a 3′-UTR of a gene selected from the group consisting of analbumin gene, an α-globin gene, a β-globin gene, a tyrosine hydroxylasegene, a lipoxygenase gene, and a collagen alpha gene, such as a collagenalpha 1(I) gene according to SEQ ID NO: 1369-1390 of the patentapplication WO 2013/143700, whose disclosure is incorporated herein byreference, or from a homolog, a fragment or a variant thereof. In aparticularly preferred embodiment, the 3′-UTR element comprises orconsists of a nucleic acid sequence which is derived from a 3′-UTR of analbumin gene, preferably a vertebrate albumin gene, more preferably amammalian albumin gene, most preferably a human albumin gene accordingto SEQ ID NO: 78355 or the corresponding RNA sequence SEQ ID NO: 78356.

Human albumin 3′-UTR SEQ ID NO: 78355:CATCACATTTAAAAGCATCTCAGCCTACCATGAGAATAAGAGAAAGAAAATGAAGATCAAAAGCTTATTCATCTGTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCTCTGT GCTTCAATTAATAAAAAATGGAAAGAATCT(corresponding to SEQ ID NO: 1369 of thepatent application WO 2013/143700).

In this context it is particularly preferred that the RNA according tothe invention comprises a 3′-UTR element comprising a corresponding RNAsequence derived from the nucleic acids according to SEQ ID NO:1369-1390 of the patent application WO 2013/143700 or a fragment,homolog or variant thereof.

Most preferably the 3′-UTR element comprises the nucleic acid sequencederived from a fragment of the human albumin gene according to SEQ IDNO: 78357 or 78359:

albumin7 3′-UTR CATCACATTTAAAAGCATCTCAGCCTACCATGAGAATAAGAGAAAGAAAATGAAGATCAATAGCTTATTCATCTCTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCTCTGTGCTTCAAT TAATAAAAAATGGAAAGAACCT(SEQ ID NO: 78357 corresponding to SEQ ID NO: 1376 of the patentapplication WO 2013/143700)

In this context, it is particularly preferred that the 3′-UTR element ofthe RNA according to the present invention comprises or consists of acorresponding RNA sequence of the nucleic acid sequence according to SEQID NO: 78357 or 78359 as shown in SEQ ID NO: 78358 or 78360.

In another particularly preferred embodiment, the 3′-UTR elementcomprises or consists of a nucleic acid sequence which is derived from a3′-UTR of an α-globin gene, preferably a vertebrate α- or β-globin gene,more preferably a mammalian α- or β-globin gene, most preferably a humanα- or β-globin gene according to SEQ ID NO: 78347, 78349 or 78351 or thecorresponding RNA sequences SEQ ID NO: 78348, 78350 or 78352:

3′-UTR of Homo sapiens hemoglobin, alpha I (HBAI)GCTGGAGCCTCGGTGGCCATGCTTCTTGCCCCTTGGGCCTCCCCCCAGCCCCTCCTCCCCTTCCTGCACCCGTACCCCCGTGGTCTTTGAATAAAG TCTGAGTGGGCGGC(SEQ ID NO: 78347 corresponding toSEQ ID NO: 1370 of the patent application WO 2013/143700)3′-UTR of Homo sapiens hemoglobin, alpha 2 (HBA2)GCTGGAGCCTCGGTAGCCGTTCCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCCCCTCCTTGCACCGGCCCTTCCTGGTCTTTGAATAAAGT CTGAGTGGGCAG(SEQ ID NO: 78349 corresponding toSEQ ID NO: 1371 of the patent application WO 2013/143700)3′-UTR of Homo sapiens hemoglobin, beta (HBB)GCTCGCTTTCTTGCTGTCCAATTTCTATTAAAGGTTCCTTTGTTCCCTAAGTCCAACTACTAAACTGGGGGATATTATGAAGGGCCTTGAGCATCTGGATTCTGCCTAATAAAAAACATTTATTTTCATTGC (SEQ ID NO: 78351 corresponding toSEQ ID NO: 1372 of the patent application WO 2013/143700) 

For example, the 3′-UTR element may comprise or consist of the center,a-complex-binding portion of the 3′-UTR of an α-globin gene, such as ofa human α-globin gene, or a homolog, a fragment, or a variant of anα-globin gene, preferably according to SEQ ID NO: 78353:

Center, α-complex-binding portion of the3′-UTR of an α-globin gene (also named herein as “muag”)GCCCGATGGGCCTCCCAACGGGCCCTCCTCCCCTCCTTGCACCG(SEQ ID NO: 78353 corresponding to SEQ ID NO: 1393 of the patentapplication WO 2013/143700). 

In this context it is particularly preferred that the 3′-UTR element ofthe RNA according to the invention comprises or consists of acorresponding RNA sequence of the nucleic acid sequence according to SEQID NO: 78353 as shown in SEQ ID NO: 78354, or a homolog, a fragment orvariant thereof.

The term “a nucleic acid sequence which is derived from the 3′-UTR of a[. . . ] gene” preferably refers to a nucleic acid sequence which isbased on the 3′-UTR sequence of a [. . . ] gene or on a part thereof,such as on the 3′-UTR of an albumin gene, an α-globin gene, a β-globingene, a tyrosine hydroxylase gene, a lipoxygenase gene, or a collagenalpha gene, such as a collagen alpha 1(I) gene, preferably of an albumingene or on a part thereof. This term includes sequences corresponding tothe entire 3′-UTR sequence, i.e. the full length 3′-UTR sequence of agene, and sequences corresponding to a fragment of the 3′-UTR sequenceof a gene, such as an albumin gene, α-globin gene, β-globin gene,tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene,such as a collagen alpha 1(I) gene, preferably of an albumin gene.

The term “a nucleic acid sequence which is derived from a variant of the3′-UTR of a [. . . ] gene” preferably refers to a nucleic acid sequence,which is based on a variant of the 3′-UTR sequence of a gene, such as ona variant of the 3′-UTR of an albumin gene, an α-globin gene, a β-globingene, a tyrosine hydroxylase gene, a lipoxygenase gene, or a collagenalpha gene, such as a collagen alpha 1(I) gene, or on a part thereof asdescribed above. This term includes sequences corresponding to theentire sequence of the variant of the 3′-UTR of a gene, i.e. the fulllength variant 3′-UTR sequence of a gene, and sequences corresponding toa fragment of the variant 3′-UTR sequence of a gene. A fragment in thiscontext preferably consists of a continuous stretch of nucleotidescorresponding to a continuous stretch of nucleotides in the full-lengthvariant 3′-UTR, which represents at least 20%, preferably at least 30%,more preferably at least 40%, more preferably at least 50%, even morepreferably at least 60%, even more preferably at least 70%, even morepreferably at least 80%, and most preferably at least 90% of thefull-length variant 3′-UTR. Such a fragment of a variant, in the senseof the present invention, is preferably a functional fragment of avariant as described herein.

In a particularly preferred embodiment, the at least one mRNA of theinventive composition comprises at least one 5′-untranslated regionelement (5′-UTR element). Preferably, the at least one 5′-UTR elementcomprises or consists of a nucleic acid sequence, which is derived fromthe 5′-UTR of a TOP gene or which is derived from a fragment, homolog orvariant of the 5′-UTR of a TOP gene.

It is particularly preferred that the 5′-UTR element does not comprise aTOP motif or a 5′TOP, as defined above.

In some embodiments, the nucleic acid sequence of the 5′-UTR element,which is derived from a 5′-UTR of a TOP gene, terminates at its 3′-endwith a nucleotide located at position 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10upstream of the start codon (e.g. A(U/T)G) of the gene or mRNA it isderived from. Thus, the 5′-UTR element does not comprise any part of theprotein coding region. Thus, preferably, the only protein coding part ofthe at least one mRNA of the inventive composition is provided by thecoding region.

The nucleic acid sequence derived from the 5′-UTR of a TOP gene ispreferably derived from a eukaryotic TOP gene, preferably a plant oranimal TOP gene, more preferably a chordate TOP gene, even morepreferably a vertebrate TOP gene, most preferably a mammalian TOP gene,such as a human TOP gene.

For example, the 5′-UTR element is preferably selected from 5′-UTRelements comprising or consisting of a nucleic acid sequence, which isderived from a nucleic acid sequence selected from the group consistingof SEQ ID NOs: 1-1363, SEQ ID NO: 1395, SEQ ID NO: 1421 and SEQ ID NO:1422 of the patent application WO 2013/143700, whose disclosure isincorporated herein by reference, from the homologs of SEQ ID NOs:1-1363, SEQ ID NO: 1395, SEQ ID NO: 1421 and SEQ ID NO: 1422 of thepatent application WO 2013/143700, from a variant thereof, or preferablyfrom a corresponding RNA sequence. The term “homologs of SEQ ID NOs:1-1363, SEQ ID NO: 1395, SEQ ID NO: 1421 and SEQ ID NO: 1422 of thepatent application WO 2013/143700” refers to sequences of other speciesthan homo sapiens, which are homologous to the sequences according toSEQ ID NO s: 1-1363, SED ID NO:1395, SEQ ID NO: 1421 and SEQ ID NO:1422of the patent application WO 2013/143700.

In a preferred embodiment, the 5′-UTR element of the RNA according tothe invention comprises or consists of a nucleic acid sequence, which isderived from a nucleic acid sequence extending from nucleotide position5 (i.e. the nucleotide that is located at position 5 in the sequence) tothe nucleotide position immediately 5′ to the start codon (located atthe 3′ end of the sequences), e.g. the nucleotide position immediately5′ to the ATG sequence, of a nucleic acid sequence selected from SEQ IDNOs: 1-1363, SEQ ID NO: 1395, SEQ ID NO: 1421 and SEQ ID NO: 1422 of thepatent application WO 2013/143700, from the homologs of SEQ ID NOs:1-1363, SEQ ID NO: 1395, SEQ ID NO: 1421 and SEQ ID NO: 1422 of thepatent application WO 2013/143700 from a variant thereof, or acorresponding RNA sequence. It is particularly preferred that the 5′-UTRelement is derived from a nucleic acid sequence extending from thenucleotide position immediately 3′ to the 5′-TOP to the nucleotideposition immediately 5′ to the start codon (located at the 3′ end of thesequences), e.g. the nucleotide position immediately 5′ to the ATGsequence, of a nucleic acid sequence selected from SEQ ID NOs: 1-1363,SEQ ID NO: 1395, SEQ ID NO: 1421 and SEQ ID NO: 1422 of the patentapplication WO 2013/143700, from the homologs of SEQ ID NOs: 1-1363, SEQID NO: 1395, SEQ ID NO: 1421 and SEQ ID NO:1422 of the patentapplication WO 2013/143700, from a variant thereof, or a correspondingRNA sequence.

In a particularly preferred embodiment, the 5′-UTR element comprises orconsists of a nucleic acid sequence, which is derived from a 5′-UTR of aTOP gene encoding a ribosomal protein or from a variant of a 5′-UTR of aTOP gene encoding a ribosomal protein. For example, the 5′-UTR elementcomprises or consists of a nucleic acid sequence, which is derived froma 5′-UTR of a nucleic acid sequence according to any of SEQ ID NOs: 67,170, 193, 244, 259, 554, 650, 675, 700, 721, 913, 1016, 1063, 1120,1138, and 1284-1360 of the patent application WO 2013/143700, acorresponding RNA sequence, a homolog thereof, or a variant thereof asdescribed herein, preferably lacking the 5′TOP motif. As describedabove, the sequence extending from position 5 to the nucleotideimmediately 5′ to the ATG (which is located at the 3′-end of thesequences) corresponds to the 5′-UTR of said sequences.

Preferably, the 5′-UTR element comprises or consists of a nucleic acidsequence, which is derived from a 5′-UTR of a TOP gene encoding aribosomal Large protein (RPL) or from a homolog or variant of a 5′-UTRof a TOP gene encoding a ribosomal Large protein (RPL). For example, the5′-UTR element comprises or consists of a nucleic acid sequence, whichis derived from a 5′-UTR of a nucleic acid sequence according to any ofSEQ ID NOs: 7, 259, 1284-1318, 1344, 1346, 1348-1354, 1357, 1358, 1421and 1422 of the patent application WO 2013/143700, a corresponding RNAsequence, a homolog thereof, or a variant thereof as described herein,preferably lacking the 5′TOP motif.

In a particularly preferred embodiment, the 5′-UTR element comprises orconsists of a nucleic acid sequence which is derived from the 5′-UTR ofa ribosomal protein Large 32 gene, preferably from a vertebrateribosomal protein Large 32 (L32) gene, more preferably from a mammalianribosomal protein Large 32 (L32) gene, most preferably from a humanribosomal protein Large 32 (L32) gene, or from a variant of the 5′-UTRof a ribosomal protein Large 32 gene, preferably from a vertebrateribosomal protein Large 32 (L32) gene, more preferably from a mammalianribosomal protein Large 32 (L32) gene, most preferably from a humanribosomal protein Large 32 (L32) gene, wherein preferably the 5′-UTRelement does not comprise the 5′ TOP of said gene.

Accordingly, in a particularly preferred embodiment, the 5′-UTR elementcomprises or consists of a nucleic acid sequence, which has an identityof at least about 40%, preferably of at least about 50%, preferably ofat least about 60%, preferably of at least about 70%, more preferably ofat least about 80%, more preferably of at least about 90%, even morepreferably of at least about 95%, even more preferably of at least about99% to the nucleic acid sequence according to SEQ ID NO: 78343 or 78344(5′-UTR of human ribosomal protein Large 32 lacking the 5′ terminaloligopyrimidine tract: GGCGCTGCCTACGGAGGTGGCAGCCATCTCCTTCTCGGCATC;corresponding to SEQ ID NO: 1368 of the patent application WO2013/143700) or preferably to a corresponding RNA sequence, or whereinthe at least one 5′-UTR element comprises or consists of a fragment of anucleic acid sequence which has an identity of at least about 40%,preferably of at least about 50%, preferably of at least about 60%,preferably of at least about 70%, more preferably of at least about 80%,more preferably of at least about 90%, even more preferably of at leastabout 95%, even more preferably of at least about 99% to the nucleicacid sequence according to SEQ ID NO: 78343 or more preferably to acorresponding RNA sequence (SEQ ID NO: 78344), wherein, preferably, thefragment is as described above, i.e. being a continuous stretch ofnucleotides representing at least 20% etc. of the full-length 5′-UTR.Preferably, the fragment exhibits a length of at least about 20nucleotides or more, preferably of at least about 30 nucleotides ormore, more preferably of at least about 40 nucleotides or more.Preferably, the fragment is a functional fragment as described herein.

In some embodiments, the RNA according to the invention comprises a5′-UTR element, which comprises or consists of a nucleic acid sequence,which is derived from the 5′-UTR of a vertebrate TOP gene, such as amammalian, e.g. a human TOP gene, selected from RPSA, RPS2, RPS3, RPS3A,RPS4, RPS5, RPS6, RPS7, RPS8; RPS9, RPS10, RPS11, RPS12, RPS13, RPS14,RPS15, RPS15A, RPS16, RPS17, RPS18, RPS19, RPS20, RPS21, RPS23, RPS24,RPS25, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS30, RPL3, RPL4, RPL5,RPL6, RPL7, RPL7A, RPL8, RPL9, RPL10, RPL10A, RPL11, RPL12, RPL13,RPL13A, RPL14, RPL15, RPL17, RPL18, RPL18A, RPL19, RPL21, RPL22, RPL23,RPL23A, RPL24, RPL26, RPL27, RPL27A, RPL28, RPL29, RPL30, RPL31, RPL32,RPL34, RPL35, RPL35A, RPL36, RPL36A, RPL37, RPL37A, RPL38, RPL39, RPL40,RPL41, RPLP0, RPLP1, RPLP2, RPLP3, RPLP0, RPLP1, RPLP2, EEF1A1, EEF1B2,EEF1D, EEF1G, EEF2, EIF3E, EIF3F, EIF3H, EIF2S3, EIF3C, EIF3K, EIF3EIP,EIF4A2, PABPC1, HNRNPA1, TPT1, TUBB1, UBA52, NPM1, ATP5G2, GNB2L1, NME2,UQCRB, or from a homolog or variant thereof, wherein preferably the5′-UTR element does not comprise a TOP motif or the 5′TOP of said genes,and wherein optionally the 5′-UTR element starts at its 5′-end with anucleotide located at position 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10downstream of the 5′terminal oligopyrimidine tract (TOP) and whereinfurther optionally the 5′-UTR element which is derived from a 5′-UTR ofa TOP gene terminates at its 3′-end with a nucleotide located atposition 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 upstream of the start codon(A(U/T)G) of the gene it is derived from.

In further particularly preferred embodiments, the 5′-UTR elementcomprises or consists of a nucleic acid sequence, which is derived fromthe 5′-UTR of a ribosomal protein Large 32 gene (RPL32), a ribosomalprotein Large 35 gene (RPL35), a ribosomal protein Large 21 gene(RPL21), an ATP synthase, H+ transporting, mitochondrial F1 complex,alpha subunit 1, cardiac muscle (ATPSA1) gene, an hydroxysteroid(17-beta) dehydrogenase 4 gene (HSD17B4), an androgen-induced 1gene(AIG1), cytochrome c oxidase subunit Vlc gene (COX6C), or aN-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1) orfrom a variant thereof, preferably from a vertebrate ribosomal proteinLarge 32 gene (RPL32), a vertebrate ribosomal protein Large 35 gene(RPL35), a vertebrate ribosomal protein Large 21 gene (RPL21), avertebrate ATP synthase, H+ transporting, mitochondrial F1 complex,alpha subunit 1, cardiac muscle (ATP5A1) gene, a vertebratehydroxysteroid (17-beth) dehydrogenase 4 gene (HSD17B4), a vertebrateandrogen-induced 1 gene (AIG1), a vertebrate cytochrome c oxidasesubunit Vlc gene (COX6C), or a vertebrate N-acylsphingosineamidohydrolase (acid ceramidase) 1 gene (ASAH1) or from a variantthereof, more preferably from a mammalian ribosomal protein Large 32gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomalprotein Large 21 gene (RPL21), a mammalian ATP synthase, H+transporting, mitochondrial F1 complex, alpha subunit 1, cardiac muscle(ATP5A1) gene, a mammalian hydroxysteroid (17-beth) dehydrogenase 4 gene(HSD17B4), a mammalian androgen-induced 1 gene (AIG1), a mammaliancyto-chrome c oxidase subunit Vlc gene (COXGC), or a mammalianN-acylsphingosine ami-dohydrolase (acid ceramidase) 1 gene (ASAH1) orfrom a variant thereof, most preferably from a human ribosomal proteinLarge 32 gene (RPL32), a human ribosomal protein Large 35 gene (RPL35),a human ribosomal protein Large 21 gene (RPL21), a human ATP syn-thase,H+ transporting, mitochondrial F1 complex, alpha subunit 1, cardiacmuscle (ATP5A1) gene, a human hydroxysteroid (17-beth) dehydrogenase 4gene (HSD17B4), a human androgen-induced 1 gene (AIG1), a humancytochrome c oxidase subunit Vlc gene (COXGC), or a humanN-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1) orfrom a variant thereof, wherein preferably the 5′-UTR element does notcomprise the 5′TOP of said gene.

Accordingly, in a particularly preferred embodiment, the 5′-UTR elementcomprises or consists of a nucleic acid sequence, which has an identityof at least about 40%, preferably of at least about 50%, preferably ofat least about 60%, preferably of at least about 70%, more preferably ofat least about 80%, more preferably of at least about 90%, even morepreferably of at least about 95%, even more preferably of at least about99% to the nucleic acid sequence according to SEQ ID NO: 1368, or SEQ IDNOs: 1412-1420 of the patent application WO 2013/143700, or acorresponding RNA sequence, or wherein the at least one 5′-UTR elementcomprises or consists of a fragment of a nucleic acid sequence which hasan identity of at least about 40%, preferably of at least about 50%,preferably of at least about 60%, preferably of at least about 70%, morepreferably of at least about 80%, more preferably of at least about 90%,even more preferably of at least about 95%, even more preferably of atleast about 99% to the nucleic acid sequence according to SEQ ID NO:1368, or SEQ ID NOs: 1412-1420 of the patent application WO 2013/143700,wherein, preferably, the fragment is as described above, i.e. being acontinuous stretch of nucleotides representing at least 20% etc. of thefull-length 5′-UTR. Preferably, the fragment exhibits a length of atleast about 20 nucleotides or more, preferably of at least about 3Dnucleotides or more, more preferably of at least about 40 nucleotides ormore. Preferably, the fragment is a functional fragment as describedherein.

Accordingly, in a particularly preferred embodiment, the 5′-UTR elementcomprises or consists of a nucleic acid sequence, which has an identityof at least about 40%, preferably of at least about 50%, preferably ofat least about 60%, preferably of at least about 70%, more preferably ofat least about 80%, more preferably of at least about 90%, even morepreferably of at least about 95%, even more preferably of at least about99% to the nucleic acid sequence according to SEQ ID NO: 78345 or 78346(5′-UTR of ATP5A1 lacking the 5′ terminal oligopyrimidine tract:GCGGCTCGGCCATTTTGTCCCAGTCAGTCCGGAGGCTGCGGCTGCAGAAGTACCGCCTGCG-GAGTAACTGCAAAG;corresponding to SEQ ID NO: 1414 of the patent application WO2013/143700) or preferably to a corresponding RNA sequence, or whereinthe at least one 5′-UTR element comprises or consists of a fragment of anucleic acid sequence which has an identity of at least about 40%,preferably of at least about 50%, preferably of at least about 60%,preferably of at least about 70%, more preferably of at least about 80%,more preferably of at least about 90%, even more preferably of at leastabout 95%, even more preferably of at least about 99% to the nucleicacid sequence according to SEQ ID NO: 2435 or more preferably to acorresponding RNA sequence (SEQ ID NO: 2436), wherein, preferably, thefragment is as described above, i.e. being a continuous stretch ofnucleotides representing at least 20% etc. of the full-length 5′-UTR.Preferably, the fragment exhibits a length of at least about 20nucleotides or more, preferably of at least about 30 nucleotides ormore, more preferably of at least about 40 nucleotides or more.Preferably, the fragment is a functional fragment as described herein.

Preferably, the at least one 5′-UTR element and the at least one 3′-UTRelement act synergistically to increase protein production from the atleast one mRNA of the inventive composition as described above.

In a particularly preferred embodiment, the RNA according to theinvention comprises a histone stem-loop sequence/structure. Such histonestem-loop sequences are preferably selected from histone stem-loopsequences as disclosed in WO 2012/019780, the disclosure of which isincorporated herewith by reference. A histone stem-loop sequence,suitable to be used within the present invention, is preferably selectedfrom at least one of the following formulae (I) or (II):

formula (I) (stem-loop sequence without stem bordering elements):

formula (II) (stem-loop sequence with stem bordering elements):

wherein:

stem1 or stem2 bordering elements N₁₋₅ is a consecutive sequence of 1 to6, preferably of 2 to 6, more preferably of 2 to 5, even more preferablyof 3 to 5, most preferably of 4 to 5 or 5 N, wherein each N isindependently from another selected from a nucleotide selected from A,U, T, G and C, or a nucleotide analogue thereof;

stem1 [N₀₋₂GN₃₋₅] is reverse complementary or partially reversecomplementary with element stem2, and is a consecutive sequence betweenof 5 to 7 nucleotides;

wherein N₀₋₂ is a consecutive sequence of 0 to 2, preferably of 0 to 1,more preferably of 1 N, wherein each N is independently from anotherselected from a nucleotide selected from A, U, T, G and C or anucleotide analogue thereof;

wherein N₀₋₅ is a consecutive sequence of 3 to 5, preferably of 4 to 5,more preferably of 4 N, wherein each N is independently from anotherselected from a nucleotide selected from A, U, T, G and C or anucleotide analogue thereof, and

wherein G is guanosine or an analogue thereof, and may be optionallyreplaced by a cytidine or an analogue thereof, provided that itscomplementary nucleotide cytidine in stem2 is replaced by guanosine;

loop sequence [N₀₋₄(U/T)N₀₋₄] is located between elements stem1 andstem2, and is a consecutive sequence of 3 to 5 nucleotides, morepreferably of 4 nucleotides;

wherein each N₀₋₄ is independent from another a consecutive sequence of0 to 4, preferably of 1 to 3, more preferably of 1 to 2 N, wherein eachN is independently from another selected from a nucleotide selected fromA, U, T, G and C or a nucleotide analogue thereof; and

wherein U/T represents uridine, or optionally thymidine;

stem2 [N₃₋₅CN₀₋₂] is reverse complementary or partially reversecomplementary with element stem1, and is a consecutive sequence betweenof 5 to 7 nucleotides;

wherein N₃₋₅ is a consecutive sequence of 3 to 5, preferably of 4 to 5,more preferably of 4 N, wherein each N is independently from anotherselected from a nucleotide selected from A, U, T, G and C or anucleotide analogue thereof;

wherein N₀₋₂ is a consecutive sequence of 0 to 2, preferably of 0 to 1,more preferably of 1 N, wherein each N is independently from anotherselected from a nucleotide selected from A, U, T, G or C or a nucleotideanalogue thereof; and

wherein C is cytidine or an analogue thereof, and may be optionallyreplaced by a guanosine or an analogue thereof provided that itscomplementary nucleoside guanosine in stem1 is replaced by cytidine;

wherein

stem1 and stem2 are capable of base pairing with each other forming areverse complementary sequence, wherein base pairing may occur betweenstem1 and stem2, e.g. by Watson-Crick base pairing of nucleotides A andU/T or G and C or by non-Watson-Crick base pairing e.g. wobble basepairing, reverse Watson-Crick base pairing, Hoogsteen base pairing,reverse Hoogsteen base pairing or are capable of base pairing with eachother forming a partially reverse complementary sequence, wherein anincomplete base pairing may occur between stem1 and stem2, on the basisthat one ore more bases in one stem do not have a complementary base inthe reverse complementary sequence of the other stem.

According to a further preferred embodiment, the RNA according to theinvention may comprise at least one histone stem-loop sequence accordingto at least one of the following specific formulae (Ia) or (IIa):

formula (Ia) (stem-loop sequence without stem bordering elements):

formula (IIa) (stem-loop sequence with stem bordering elements):

wherein: N, C, G, T and U are as defined above.

According to a further more particularly preferred embodiment, the RNAaccording to the invention may comprise at least one histone stem-loopsequence according to at least one of the following specific formulae(Ib) or (IIb):

formula (Ib) (stem-loop sequence without stem bordering elements):

formula (IIb) (stem-loop sequence with stem bordering elements):

wherein: N, C, G, T and U are as defined above.

A particularly preferred histone stem-loop sequence is the sequenceCAAAGGCTCTTTTCAGAGCCACCA (according to SEQ ID NO: 78361) or morepreferably the corresponding RNA sequence CAAAGGCUCUUUUUCAGAGCCACCA(according to SEQ ID NO: 78362).

According to another particularly preferred embodiment, the RNAaccording to the invention may additionally or alternatively encode asecretory signal peptide. Such signal peptides are sequences, whichtypically exhibit a length of about 15 to 30 amino acids and arepreferably located at the N-terminus of the encoded peptide, withoutbeing limited thereto. Signal peptides as defined herein preferablyallow the transport of the therapeutic protein as encoded by the atleast one mRNA of the composition into a defined cellular compartiment,preferably the cell surface, the endoplasmic reticulum (ER) or theendosomal-lysosomal compartiment. Examples of secretory signal peptidesequences as defined herein include, without being limited thereto,signal sequences of classical or non-classical MHC-molecules (e.g.signal sequences of MHC I and II molecules, e.g. of the MHC class Imolecule HLA-A*0201), signal sequences of cytokines or immunoglobulinesas defined herein, signal sequences of the invariant chain ofimmunoglobulines or antibodies as defined herein, signal sequences ofLamp1, Tapasin, Erp57, Calretikulin, Calnexin, and further membraneassociated proteins or of proteins associated with the endoplasmicreticulum (ER) or the endosomal-lysosomal compartiment. Most preferably,signal sequences of MHC class I molecule HLA-A*0201 may be usedaccording to the present invention. For example, a signal peptidederived from HLA-A is preferably used in order to promote secretion ofthe encoded therapeutic protein as defined herein or a fragment orvariant thereof. More preferably, an HLA-A signal peptide is fused to anencoded therapeutic protein as defined herein or to a fragment orvariant thereof:

Any of the above modifications may be applied to the RNA of the presentinvention, and further to any RNA as used in the context of the presentinvention and may be, if suitable or necessary, be combined with eachother in any combination, provided, these combinations of modificationsdo not interfere with each other in the respective at least one mRNA. Aperson skilled in the art will be able to take his choice accordingly.

The RNA, preferably an mRNA, according to the invention, which comprisesat least one coding sequence as defined herein, may preferably comprisea 5′-UTR and/or a 3′-UTR preferably containing at least one histonestem-loop. Where, in addition to the therapeutic protein as definedherein or a fragment or variant thereof, a further peptide or protein isencoded by the at least one coding sequence of the RNA according to theinvention, the encoded peptide or protein is preferably no histoneprotein, no reporter protein and/or no marker or selection protein, asdefined herein. The 3′-UTR of the RNA according to the inventionpreferably comprises also a poly(A) and/or a poly(C) sequence as definedherein. The single elements of the 3′-UTR may occur therein in any orderfrom 5′ to 3′ along the sequence of the RNA of the present invention. Inaddition, further elements as described herein, may also be contained,such as a stabilizing sequence as defined herein (e.g. derived from theUTR of a globin gene), IRES sequences, etc. Each of the elements mayalso be repeated in the RNA according to the invention at least once(particularly in di- or multicistronic constructs), preferably twice ormore. As an example, the single elements may be present in the RNAaccording to the invention in the following order:

5′—coding region—histone stem-loop—poly(A)/(C) sequence—3′; or

5′—coding region—poly(A)/(C) sequence—histone stem-loop—3′; or

5′—coding region—histone stem-loop—polyadenylation signal—3′; or

5′—coding region—polyadenylation signal—histone stem-loop—3′; or

5′—coding region—histone stem-loop—histone stem-loop—poly(A)/(C)sequence—3′; or

5′—coding region—histone stem-loop—histone stem-loop—polyadenylationsignal—3′; or

5′—coding region—stabilizing sequence—poly(A)/(C) sequence—histonestem-loop—3′; or

5′—coding region—stabilizing sequence—poly(A)/(C) sequence—poly(A)/(C)sequence—histone stem-loop—3′; etc.

According to a further embodiment, the RNA, preferably an mRNA, of thepresent invention preferably comprises at least one of the followingstructural elements: a 5′- and/or 3′-untranslated region element (UTRelement), particularly a 5′-UTR element, which preferably comprises orconsists of a nucleic acid sequence which is derived from the 5′-UTR ofa TOP gene or from a fragment, homolog or a variant thereof, or a 5′-and/or 3′-UTR element which may preferably be derivable from a gene thatprovides a stable mRNA or from a homolog, fragment or variant thereof; ahistone-stem-loop structure, preferably a histone-stem-loop in its 3′untranslated region; a 5′-cap structure; a poly-A tail; or a poly(C)sequence.

According to some embodiments, it is particularly preferred that—if, inaddition to an therapeutic protein as defined herein or a fragment orvariant thereof, a further peptide or protein is encoded by the at leastone coding sequence as defined herein—the encoded peptide or protein ispreferably no histone protein, no reporter protein (e.g. Luciferase,GFP, EGFP, (3-Galactosidase, particularly EGFP) and/or no marker orselection protein (e.g. alpha-Globin, Galactokinase and Xanthine:Guaninephosphoribosyl transferase (GPT)). In a preferred embodiment, the RNAaccording to the invention does not comprise a reporter gene or a markergene. Preferably, the RNA according to the invention does not encode,for instance, luciferase; green fluorescent protein (GFP) and itsvariants (such as eGFP, RFP or BFP); α-globin; hypoxanthine-guaninephosphoribosyltransferase (HGPRT); β-galactosidase; galactokinase;alkaline phosphatase; secreted embryonic alkaline phosphatase (SEAP)) ora resistance gene (such as a resistance gene against neomycin,puromycin, hygromycin and zeocin). In a preferred embodiment, the RNAaccording to the invention does not encode luciferase. In anotherembodiment, the RNA according to the invention does not encode GFP or avariant thereof.

According to a preferred embodiment, the RNA according to the presentinvention comprises, preferably in 5′ to 3′ direction, the followingelements:

-   -   a) a 5′-CAP structure, preferably m7GpppN,    -   b) at least one coding sequence comprising or consisting of any        one of the nucleic acid sequences selected from the group        consisting of nucleic acid sequences according to any one of SEQ        ID NO:13058 to 78342, or a fragment or variant thereof,    -   c) a poly(A) tail, preferably consisting of 10 to 200, 10 to        100, 40 to 80 or 50 to 70 adenosine nucleotides,    -   d) a poly(C) tail, preferably consisting of 10 to 200, 10 to        100, 20 to 70, 20 to 60 or 10 to 40 cytosine nucleotides, and    -   e) a histone stem-loop, preferably comprising the RNA sequence        according to SEQ ID NO: 78362.

More preferably, the RNA according to the invention comprises,preferably in 5′ to 3′ direction, the following elements:

-   -   a) a 5′-CAP structure, preferably m7GpppN,    -   b) at least one coding sequence comprising or consisting of any        one of the nucleic acid sequences selected from the group        consisting of nucleic acid sequences according to any one of SEQ        ID NO:13058 to 78342, or a fragment or variant thereof,    -   c) a 3′-UTR element comprising a nucleic acid sequence, which is        derived from an α-globin gene, preferably comprising the        corresponding RNA sequence of the nucleic acid sequence        according to SEQ ID NO: 78353, or a homolog, a fragment or a        variant thereof,    -   d) a poly(A) tail, preferably consisting of 10 to 200, 10 to        100, 40 to 80 or 50 to 70 adenosine nucleotides,    -   e) a poly(C) tail, preferably consisting of 10 to 200, 10 to        100, 20 to 70, 20 to 60 or 10 to 40 cytosine nucleotides, and    -   f) a histone stem-loop, preferably comprising the RNA sequence        according to SEQ ID NO: 78362.

In a further embodiment, the RNA according to the invention comprises,preferably in 5′ to 3′ direction, the following elements:

-   -   a) a 5′-CAP structure, preferably m7GpppN,    -   b) a 5′-UTR element, which preferably comprises or consists of a        nucleic acid sequence, which is derived from the 5′-UTR of a TOP        gene, preferably comprising an RNA sequence corresponding to the        nucleic acid sequence according to SEQ ID NO: 78343, or a        homolog, a fragment or a variant thereof,    -   c) at least one coding sequence comprising or consisting of any        one of the nucleic acid sequences selected from the group        consisting of nucleic acid sequences according to any one of SEQ        ID NO: 13058 to 78342, or a fragment or variant thereof,    -   d) a 3′-UTR element comprising a nucleic acid sequence, which is        preferably derived from an α-globin gene, preferably comprising        the corresponding RNA sequence of the nucleic acid sequence        according to SEQ ID ND: 78353, or a homolog, a fragment or a        variant thereof; and/or        -   a 3′-UTR element comprising a nucleic acid sequence, which            is derived from an albumin gene, preferably comprising the            corresponding RNA sequence of the nucleic acid sequence            according to SEQ ID NO: 78357, or a homolog, a fragment or a            variant thereof,    -   e) a poly(A) tail, preferably consisting of 10 to 200, 10 to        100, 40 to 80 or 50 to 70 adenosine nucleotides,    -   f) a poly(C) tail, preferably consisting of 10 to 200, 10 to        100, 20 to 70, 20 to 60 or 10 to 40 cytosine nucleotides, and    -   g) a histone stem-loop, preferably comprising the RNA sequence        according to SEQ ID NO: 78362.

The RNA according to the present invention may be prepared using anymethod known in the art, including synthetic methods such as e.g. solidphase RNA synthesis, as well as in vitro methods, such as RNA invitratranscription reactions.

In a further aspect, the present invention concerns a compositioncomprising the RNA comprising at least one coding sequence as definedherein and a pharmaceutically acceptable carrier. The compositionaccording to the invention is preferably provided as a pharmaceuticalcomposition.

According to a preferred embodiment, the (pharmaceutical) compositionaccording to the invention comprises the RNA of the present invention,wherein the at least one coding sequence of the RNA encodes a peptide orprotein comprising or consisting of any one of the therapeutic proteinsdefined herein, preferably a peptide or protein as specified in Table 1,more preferably as defined feature c1 or feature c2 of Table 1, or afragment or variant of any one of these proteins.

Preferably, the (pharmaceutical) composition according to the inventioncomprises the RNA of the present invention, wherein the at least onecoding sequence of the RNA comprises or consists of a nucleic acidsequence encoding a therapeutic protein, or a fragment or variant of atherapeutic protein, wherein the therapeutic protein preferablycomprises or consists of any one of the amino acid sequences defined inTable 1 herein, preferably in feature c3 of Table 1, or a fragment orvariant of any one of these sequences.

Preferably, the (pharmaceutical) composition according to the inventioncomprises the RNA of the present invention, wherein the at least onecoding sequence of the RNA comprises or consists of a nucleic acidsequence encoding a therapeutic protein, or a fragment or variant of atherapeutic protein, wherein the therapeutic protein preferablycomprises or consists of an amino acid sequence having a sequenceidentity of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%,preferably of at least 70%, more preferably of at least 80%, even morepreferably at least 85%, even more preferably of at least 90% and mostpreferably of at least 95% or even 97%, with any one of the amino acidsequences defined in feature c3 of Table 1, or a fragment or variant ofany one of these sequences.

More preferably, the (pharmaceutical) composition according to theinvention comprises the RNA of the present invention, wherein the atleast one coding sequence of the RNA comprises or consists of a nucleicacid sequence encoding a therapeutic protein, or a fragment or variantof a therapeutic protein, wherein the therapeutic protein preferablycomprises or consists of an amino acid sequence having a sequenceidentity of at least 80% with any one of the amino acid sequencesdefined in feature c3 of Table 1, or a fragment or variant of any one ofthese sequences.

In preferred embodiments, the (pharmaceutical) composition according tothe invention comprises the RNA of the present invention, wherein the atleast one coding sequence of the RNA comprises or consists of any one ofthe nucleic acid sequences defined in feature c4 of Table 1, or afragment or variant of any one of these sequences.

According to another embodiment, the (pharmaceutical) compositionaccording to the invention comprises the RNA of the present invention,wherein the at least one coding sequence of the RNA comprises orconsists of a nucleic acid sequence having a sequence identity of atleast 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably ofat least 70%, more preferably of at least 80%, even more preferably atleast 85%, even more preferably of at least 90% and most preferably ofat least 95% or even 97%, with any one of the nucleic acid sequencesdefined in feature c4 of Table 1, or a fragment or variant of any one ofthese sequences.

According to a particularly preferred embodiment, the (pharmaceutical)composition according to the invention comprises the RNA of the presentinvention, wherein the at least one coding sequence of the RNA comprisesor consists of a nucleic acid sequence having a sequence identity of atleast 80% with any one of the nucleic acid sequences defined in featurec4 of Tablet or a fragment or variant of any one of these sequences.

In the context of the present invention, the (pharmaceutical)composition may encode one or more of the therapeutic proteins definedherein, or a fragment or variant thereof.

The (pharmaceutical) composition according to the invention may thuscomprise the RNA of the present invention, wherein the RNA encodes onespecific therapeutic protein of the therapeutic proteins defined herein,or a fragment or a variant thereof. In that embodiment, the(pharmaceutical) composition preferably comprises the RNA according tothe invention comprising the at least one coding sequence as definedherein encoding a peptide or protein comprising or consisting of thetherapeutic protein, or a fragment or variant thereof.

Alternatively, the (pharmaceutical) composition of the present inventionmay comprise at least one RNA according to the invention, wherein the atleast one RNA encodes at least two, three, four, five, six, seven,eight, nine, ten, eleven or twelve distinct therapeutic proteins asdefined herein or a fragment or variant thereof. Preferably, the(pharmaceutical) composition comprises several species of the RNAaccording to the invention, wherein each RNA species encodes one of thetherapeutic proteins or a fragment or variant thereof. In anotherembodiment, the RNA comprised in the (pharmaceutical) composition is abi- or multicistronic RNA as defined herein, which encodes the at leasttwo, three, four, five, six, seven, eight, nine, ten, eleven or twelvedistinct therapeutic proteins. Mixtures between these embodiments arealso envisaged, such as compositions comprising more than one RNAspecies, wherein at least one RNA species may be monocistronic, while atleast one other RNA species may be bi- or multicistronic.

The (pharmaceutical) composition according to the present invention,preferably the at least one coding sequence of the RNA comprisedtherein, may thus comprise any combination of the nucleic acid sequencesas defined herein.

In a preferred embodiment of the composition according to the invention,the RNA is complexed with one or more cationic or polycationiccompounds, preferably with cationic or polycationic polymers, cationicor polycationic peptides or proteins, e.g. protamine, cationic orpolycationic polysaccharides and/or cationic or polycationic lipids.

According to a preferred embodiment, the RNA of the compositionaccording to the present invention may be complexed with lipids to formone or more liposomes, lipoplexes, or lipid nanoparticles. Therefore, inone embodiment, the inventive composition comprises liposomes,lipoplexes, and/or lipid nanoparticles comprising the at least one mRNA.

Lipid-based formulations have been increasingly recognized as one of themost promising delivery systems for RNA due to their biocompatibilityand their ease of large-scale production. Cationic lipids have beenwidely studied as synthetic materials for delivery of RNA. After mixingtogether, nucleic acids are condensed by cationic lipids to formlipid/nucleic acid complexes known as lipoplexes. These lipid complexesare able to protect genetic material from the action of nucleases anddeliver it into cells by interacting with the negatively charged cellmembrane. Lipoplexes can be prepared by directly mixing positivelycharged lipids at physiological pH with negatively charged nucleicacids.

Conventional liposomes consist of a lipid bilayer that can be composedof cationic, anionic, or neutral (phospho)lipids and cholesterol, whichencloses an aqueous core. Both the lipid bilayer and the aqueous spacecan incorporate hydrophobic or hydrophilic compounds, respectively.Liposome characteristics and behaviour in vivo can be modified byaddition of a hydrophilic polymer coating, e.g. polyethylene glycol(PEG), to the liposome surface to confer steric stabilization.Furthermore, liposomes can be used for specific targeting by attachingligands (e.g., antibodies, peptides, and carbohydrates) to its surfaceor to the terminal end of the attached PEG chains (Front Pharmacol. 2015Dec. 1; 8:288).

Liposomes are colloidal lipid-based and surfactant-based deliverysystems composed of a phospholipid bilayer surrounding an aqueouscompartment. They may present as spherical vesicles and can range insize from 20 nm to a few microns. Cationic lipid-based liposomes areable to complex with negatively charged nucleic acids via electrostaticinteractions, resulting in complexes that offer biocompatibility, lowtoxicity, and the possibility of the large-scale production required forin vivo clinical applications. Liposomes can fuse with the plasmamembrane for uptake; once inside the cell, the liposomes are processedvia the endocytic pathway and the genetic material is then released fromthe endosome/carrier into the cytoplasm. Liposomes have long beenperceived as drug delivery vehicles because of their superiorbiocompatibility, given that liposomes are basically analogs ofbiological membranes, and can be prepared from both natural andsynthetic phospholipids (Int J Nanomedicine. 2014; 9:1833-1843).

Cationic liposomes have been traditionally the most commonly usednon-viral delivery systems for oligonucleotides, including plasmid DNA,antisense oligos, and siRNA/small hairpin RNA-shRNA). Cationic lipids,such as DOTAP, (1,2-dioleoyl-3-trimethylammonium-propane) and DOTMA(N[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethyl-ammonium methyl sulfate)can form complexes or lipoplexes with negatively charged nucleic acidsto form nanoparticles by electrostatic interaction, providing high invitro transfection efficiency. Furthermore, neutral lipid-basednanoliposomes for RNA delivery as e.g. neutral1,2-dioleoyl-sn-glycero-3- phosphatidylcholine (DOPC)-basednanoliposomes were developed. (Adv Drug Deliv Rev. 2014 February; 88:110-116).

Therefore, in one embodiment the RNA of the composition according to thepresent invention is complexed with cationic lipids and/or neutrallipids and thereby forms liposomes, lipid nanoparticles, lipoplexes orneutral lipid-based nanoliposomes.

In a preferred embodiment, the composition according to the inventioncomprises the RNA according to the invention that is formulated togetherwith a cationic or polycationic compound and/or with a polymericcarrier. Accordingly, in a further embodiment of the invention, it ispreferred that the RNA as defined herein or any other nucleic acidcomprised in the inventive (pharmaceutical) composition is associatedwith or complexed with a cationic or polycationic compound or apolymeric carrier, optionally in a weight ratio selected from a range ofabout 6:1 (w/w) to about 0.25:1 (w/w), more preferably from about 5:1(w/w) to about 0.5:1 (w/w), even more preferably of about 4:1 (w/w) toabout 1:1 (w/w) or of about 3:1 (w/w) to about 1:1 (w/w), and mostpreferably a ratio of about 3:1 (w/w) to about 2:1 (w/w) of mRNA ornucleic acid to cationic or polycationic compound and/or with apolymeric carrier; or optionally in a nitrogen/phosphate (N/P) ratio ofmRNA or nucleic acid to cationic or polycationic compound and/orpolymeric carrier in the range of about 0.1-10, preferably in a range ofabout 0.3-4 or 0.3-1, and most preferably in a range of about 0.5-1 or0.7-1, and even most preferably in a range of about 0.3-0.9 or 0.5-0.9.More preferably, the N/P ratio of the at least one mRNA to the one ormore polycations is in the range of about 0.1 to 10, including a rangeof about 0.3 to 4, of about 0.5 to 2, of about 0.7 to 2 and of about 0.7to 1.5.

Therein, the RNA as defined herein or any other nucleic acid comprisedin the (pharmaceutical) composition according to the invention can alsobe associated with a vehicle, transfection or complexation agent forincreasing the transfection efficiency and/or the expression of the RNAaccording to the invention or of optionally comprised further includednucleic acids.

Cationic or polycationic compounds, being particularly preferred agentsin this context include protamine, nucleoline, spermine or spermidine,or other cationic peptides or proteins, such as poly-L-lysine (PLL),poly-arginine, basic polypeptides, cell penetrating peptides (CPPs),including HIV-binding peptides, HIV-1 Tat (HIV), Tat-derived peptides,Penetratin, VP22 derived or analog peptides, HSV VP22 (Herpes simplex),MAP, KALA or protein transduction domains (PTDs), PpT620, prolin-richpeptides, arginine-rich peptides, lysine-rich peptides, MPG-peptide(s),Pep-1, L-oligomers, Calcitonin peptide(s), Antennapedia-derived peptides(particularly from Drosophila antomapodia), pAntp, plsl, FGF,Lactoferrin, Transportan, Buforin-2, Bac715-24, SynB, SynB(1), pVEC,hCT-derived peptides, SAP, or histones. More preferably, the RNAaccording to the invention is complexed with one or more polycations,preferably with protamine or oligofectamine, most preferably withprotamine. In this context protamine is particularly preferred.

Additionally, preferred cationic or polycationic proteins or peptidesmay be selected from the following proteins or peptides having thefollowing total formula (III):

(Arg)_(l);(Lys)_(m);(His)_(n);(Orn)_(a);(Xaa)_(x)  formula (III)

wherein l+m+n+o+x=8-15, and l, m, n or o independently of each other maybe any number selected from 0,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14 or 15, provided that the overall content of Arg, Lys, His and Ornrepresents at least 50% of all amino acids of the oligopeptide; and Xaamay be any amino acid selected from native (=naturally occurring) ornon-native amino acids except of Arg, Lys, His or Urn; and x may be anynumber selected from 0,1, 2, 3 or 4, provided, that the overall contentof Xaa does not exceed 50% of all amino acids of the oligopeptide.Particularly preferred cationic peptides in this context are e.g. Arg₇,Arg₈, Arg₉, H₃R₉, R₉H₃, H₃R₉H₃, YSSR₉SSY, (RKH)₄, Y(RKH)₂R, etc. In thiscontext the disclosure of WO 2009/030481 is incorporated herewith byreference.

Further preferred cationic or polycationic compounds, which can be usedas transfection or complexation agent may include cationicpolysaccharides, for example chitosan, polybrene, cationic polymers,e.g. polyethyleneimine (PEI), cationic lipids, e.g. DOTMA:[1-(2,3-sioleyloxy)propyl)]-N,N,N-trimethylammonium chloride, DMRIE,di-C14-amidine, DOTIM, SAINT, DC-Chol, BGTC, CTAP, DOPC, DODAP, DOPE:Dioleyl phosphatidylethanol-amine, DOSPA, DODAB, DOIC, DMEPC, DOGS:Dioctadecylamidoglicylspermin, DIMRI: Dimyristo-oxypropyl dimethylhydroxyethyl ammonium bromide, DOTAP:dioleoyloxy-3-(trimethylammonio)propane, DC-6-14:0,0-ditetradecanoyl-N-(α-trimethylammonioacetyl)diethanolamine chloride,CLIP1: rac-[(2,3-dioctadecyloxypropyl)(2-hydroxyethyl)]-dimethylammoniumchloride, CLIP6:rac-[2(2,3-dihexadecyloxypropyl-oxymethyloxy)ethyl]trimethylammonium,CLIP9:rac-[2(2,3-dihexadecyloxypropyl-oxysuccinyloxy)ethyl]-trimethylammonium,oligofectamine, or cationic or polycationic polymers, e.g. modifiedpolyaminoacids, such as β-aminoacid-polymers or reversed polyamides,etc., modified polyethylenes, such as PVP(poly(N-ethyl-4-vinylpyridinium bromide)), etc., modified acrylates,such as pDMAEMA (poly(dimethylaminoethyl methylacrylate)), etc.,modified amidoamines such as pAMAM (poly(amidoamine)), etc., modifiedpolybetaaminoester (PBAE), such as diamine end modified 1,4 butanedioldiacrylate-co-5-amino-1-pentanol polymers, etc., dendrimers, such aspolypropylamine dendrimers or pAMAM based dendrimers, etc.,polyimine(s), such as PEI: poly(ethyleneimine), poly(propyleneimine),etc., polyallylamine, sugar backbone based polymers, such ascyclodextrin based polymers, dextran based polymers, chitosan, etc.,silan backbone based polymers, such as PMOXA-PDMS copolymers, etc.,blockpolymers consisting of a combination of one or more cationic blocks(e.g. selected from a cationic polymer as mentioned above) and of one ormore hydrophilic or hydrophobic blocks (e.g. polyethyleneglycole); etc.

According to a preferred embodiment, the composition of the presentinvention comprises the RNA as defined herein and a polymeric carrier. Apolymeric carrier used according to the invention might be a polymericcarrier formed by disulfide-crosslinked cationic components. Thedisulfide-crosslinked cationic components may be the same or differentfrom each other. The polymeric carrier can also contain furthercomponents. It is also particularly preferred that the polymeric carrierused according to the present invention comprises mixtures of cationicpeptides, proteins or polymers and optionally further components asdefined herein, which are crosslinked by disulfide bonds as describedherein. In this context, the disclosure of WO 2012/013326 isincorporated herewith by reference.

In this context, the cationic components, which form basis for thepolymeric carrier by disulfide-crosslinkage, are typically selected fromany suitable cationic or polycationic peptide, protein or polymersuitable for this purpose, particular any cationic or polycationicpeptide, protein or polymer capable of complexing the RNA as definedherein or a further nucleic acid comprised in the composition, andthereby preferably condensing the RNA or the nucleic acid. The cationicor polycationic peptide, protein or polymer, is preferably a linearmolecule, however, branched cationic or polycationic peptides, proteinsor polymers may also be used.

Every disulfide-crosslinking cationic or polycationic protein, peptideor polymer of the polymeric carrier, which may be used to complex theRNA according to the invention or any further nucleic acid comprised inthe (pharmaceutical) composition of the present invention contains atleast one —SH moiety, most preferably at least one cysteine residue orany further chemical group exhibiting an —SH moiety, capable of forminga disulfide linkage upon condensation with at least one further cationicor polycationic protein, peptide or polymer as cationic component of thepolymeric carrier as mentioned herein.

As defined above, the polymeric carrier, which may be used to complexthe RNA of the present invention or any further nucleic acid comprisedin the (pharmaceutical) composition according to the invention may beformed by disulfide-crosslinked cationic (or polycationic) components.Preferably, such cationic or polycationic peptides or proteins orpolymers of the polymeric carrier, which comprise or are additionallymodified to comprise at least one —SH moiety, are selected from,proteins, peptides and polymers as defined herein for complexationagent.

In a further particular embodiment, the polymeric carrier which may beused to complex the RNA as defined herein or any further nucleic acidcomprised in the (pharmaceutical) composition according to the inventionmay be selected from a polymeric carrier molecule according to genericformula (IV):

L-P¹—S—[S—P²—S]₂—S—P³-L  formula (IV)

wherein,

P¹ and P² are different or identical to each other and represent alinear or branched hydrophilic polymer chain, each P¹ and P² exhibitingat least one —SH-moiety, capable to form a disulfide linkage uponcondensation with component P², or alternatively with (AA), (AA), or[(AA)_(x)]_(z) if such components are used as a linker between P¹ and P²or P³ and P²) and/or with further components (e.g. (AA), (AA)_(x),[(AA)_(x)]_(z), or L), the linear or branched hydrophilic polymer chainselected independent from each other from polyethylene glycol (PEG),poly-N-(2-hydroxypropyl)methacrylamide, poly-2-(methacryloyloxy)ethylphosphorylcholines, poly(hydroxyalkyl L-asparagine),poly(2-(methacryloyloxy)ethyl phosphorylcholine), hydroxyethylstarch orpoly(hydroxyalkyl L-glutamine), wherein the hydrophilic polymer chainexhibits a molecular weight of about 1 kDa to about 100 kDa, preferablyof about 2 kDa to about 25 kDa; or more preferably of about 2 kDa toabout 10 kDa, e.g. about 5 kDa to about 25 kDa or 5 kDa to about 10 kDa;

P² is a cationic or polycationic peptide or protein, e.g. as definedabove for the polymeric carrier formed by disulfide-crosslinked cationiccomponents, and preferably having a length of about 3 to about 100 aminoacids, more preferably having a length of about 3 to about 50 aminoacids, even more preferably having a length of about 3 to about 25 aminoacids, e.g. a length of about 3 to 10, 5 to 15, 10 to 20 or 15 to 25amino acids, more preferably a length of about 5 to about 20 and evenmore preferably a length of about 10 to about 20; or

is a cationic or polycationic polymer, e.g. as defined above for thepolymeric carrier formed by disulfide-crosslinked cationic components,typically having a molecular weight of about 0.5 kDa to about 30 kDa,including a molecular weight of about 1 kDa to about 20 kDa, even morepreferably of about 1.5 kDa to about 10 kDa, or having a molecularweight of about 0.5 kDa to about 100 kDa, including a molecular weightof about 10 kDa to about 50 kDa, even more preferably of about 10 kDa toabout 30 kDa; each P² exhibiting at least two —SH-moieties, capable toform a disulfide linkage upon condensation with further components P² orcomponent(s) P¹ and/or P³ or alternatively with further components (e.g.(AA), (AA)_(x), or [(AA)_(x)]_(z));

—S-S— is a (reversible) disulfide bond (the brackets are omitted forbetter readability), wherein S preferably represents sulphur or a —SHcarrying moiety, which has formed a (reversible) disulfide bond. The(reversible) disulfide bond is preferably formed by condensation of—SH-moieties of either components P¹ and P², P² and P², or P² and P³, oroptionally of further components as defined herein (e.g. L, (AA),(AA)_(x), [(AA)_(x)]_(z), etc); The —SH-moiety may be part of thestructure of these components or added by a modification as definedbelow

L is an optional ligand, which may be present or not, and may beselected independent from the other from RGD, Transferrin, Folate, asignal peptide or signal sequence, a localization signal or sequence, anuclear localization signal or sequence (NLS), an antibody, a cellpenetrating peptide, (e.g. TAT or KALA), a ligand of a receptor (e.g.cytokines, hormones, growth factors etc), small molecules (e.g.carbohydrates like mannose or galactose or synthetic ligands), smallmolecule agonists, inhibitors or antagonists of receptors (e.g. RGDpeptidomimetic analogues), or any further protein as defined herein,etc.

n is an integer, typically selected from a range of about 1 to 50,preferably from a range of about 1, 2 or 3 to 30, more preferably from arange of about 1, 2, 3, 4, or 5 to 25, or a range of about 1, 2, 3, 4,or 5 to 20, or a range of about 1, 2, 3, 4, or 5 to 15, or a range ofabout 1, 2, 3, 4, or 5 to 10, including e.g. a range of about 4 to 9, 4to 10, 3 to 20, 4 to 20, 5 to 20, or 10 to 20, or a range of about 3 to15, 4 to 15, 5 to 15, or 10 to 15, or a range of about 6 to 11 or 7 to10. Most preferably, n is in a range of about 1, 2, 3, 4, or 5 to 10,more preferably in a range of about 1, 2, 3, or 4 to 9, in a range ofabout 1, 2, 3, or 4 to 8, or in a range of about 1, 2, or 3 to 7.

In this context, the disclosure of WO 2011/026641 is incorporatedherewith by reference. Each of hydrophilic polymers P¹ and P² typicallyexhibits at least one —SH-moiety, wherein the at least one —SH-moiety iscapable to form a disulfide linkage upon reaction with component P² orwith component (AA) or (AA)_(x), if used as linker between P¹ and P² orP³ and P² as defined below and optionally with a further component, e.g.L and/or (AA) or (AA)_(x), e.g. if two or more —SH-moieties arecontained. The following subformulae “P¹—S-S—P²” and “P²—S-S—P²” withingeneric formula (IV) above (the brackets are omitted for betterreadability), wherein any of S, P¹ and P³ are as defined herein,typically represent a situation, wherein one-SH-moiety of hydrophilicpolymers P¹ and P³ was condensed with one —SH-moiety of component P² ofgeneric formula (IV) above, wherein both sulphurs of these —SH-moietiesform a disulfide bond —S-S— as defined herein in formula (IV). These—SH-moieties are typically provided by each of the hydrophilic polymersP¹ and P³, e.g. via an internal cysteine or any further (modified) aminoacid or compound which carries a —SH moiety. Accordingly, thesubformulae “P¹—S-S—P²” and “P²—S-S—P³” may also be written as“P¹-Cys-Cys-P²” and “r-Cys-Cys-P³”, if the —SH— moiety is provided by acysteine, wherein the term Cys-Cys represents two cysteines coupled viaa disulfide bond, not via a peptide bond. In this case, the term “—S-S—”in these formulae may also be written as “—S-Cys”, as “-Cys-S” or as“-Cys-Cys-”. In this context, the term “-Cys-Cys-” does not represent apeptide bond but a linkage of two cysteines via their —SH-moieties toform a disulfide bond. Accordingly, the term “-Cys-Cys-” also may beunderstood generally as “-(Cys-S)-(S-Cys)-”, wherein in this specificcase S indicates the sulphur of the —SH-moiety of cysteine. Likewise,the terms “—S-Cys” and “-Cys-S” indicate a disulfide bond between a —SHcontaining moiety and a cysteine, which may also be written as“—S—(S-Cys)” and “-(Cys-S)—S”. Alternatively, the hydrophilic polymersP¹ and P³ may be modified with a —SH moiety, preferably via a chemicalreaction with a compound carrying a —SH moiety, such that each of thehydrophilic polymers P¹ and P³ carries at least one such —SH moiety.Such a compound carrying a —SH moiety may be e.g. an (additional)cysteine or any further (modified) amino acid, which carries a —SHmoiety. Such a compound may also be any non-amino compound or moiety,which contains or allows to introduce a —SH moiety into hydrophilicpolymers P¹ and P³ as defined herein. Such non-amino compounds may beattached to the hydrophilic polymers P¹ and P³ of formula (IV) of thepolymeric carrier according to the present invention via chemicalreactions or binding of compounds, e.g. by binding of a 3-thio propionicacid or thioimolane, by amide formation (e.g. carboxylic acids,sulphonic acids, amines, etc), by Michael addition (e.g maleinimidemoieties, α,β-unsatured carbonyls, etc), by click chemistry (e.g. azidesor alkines), by alkene/alkine methatesis (e.g. alkenes or alkines),imine or hydrozone formation (aldehydes or ketons, hydrazins,hydroxylamins, amines), complexation reactions (avidin, biotin, proteinG) or components which allow S_(n)-type substitution reactions (e.ghalogenalkans, thiols, alcohols, amines, hydrazines, hydrazides,sulphonic acid esters, oxyphosphonium salts) or other chemical moietieswhich can be utilized in the attachment of further components. Aparticularly preferred PEG derivate in this context isalpha-Methoxy-omega-mercapto poly(ethylene glycol). In each case, theSH-moiety, e.g. of a cysteine or of any further (modified) amino acid orcompound, may be present at the terminal ends or internally at anyposition of hydrophilic polymers P¹ and P³. As defined herein, each ofhydrophilic polymers P¹ and P³ typically exhibits at least one—SH-moiety preferably at one terminal end, but may also contain two oreven more —SH-moieties, which may be used to additionally attach furthercomponents as defined herein, preferably further functional peptides orproteins e.g. a ligand, an amino acid component (AA) or (AA)_(x),antibodies, cell penetrating peptides or enhancer peptides (e.g. TAT,KALA), etc.

Preferably, the inventive composition comprises at least one RNA asdefined herein, which is complexed with one or more polycations, and atleast one free RNA, wherein the at least one complexed RNA is preferablyidentical to the at least one free RNA. In this context, it isparticularly preferred that the composition of the present inventioncomprises the RNA according to the invention that is complexed at leastpartially with a cationic or polycationic compound and/or a polymericcarrier, preferably cationic proteins or peptides. In this context, thedisclosure of WO 2010/037539 and WO 2012/113513 is incorporated herewithby reference. Partially means that only a part of the RNA as definedherein is complexed in the composition according to the invention with acationic compound and that the rest of the RNA as defined herein is(comprised in the inventive (pharmaceutical) composition) in uncomplexedform (“free”). Preferably, the molar ratio of the complexed RNA to thefree RNA is selected from a molar ratio of about 0.001:1 to about1:0.001, including a ratio of about 1:1. More preferably the ratio ofcomplexed RNA to free RNA (in the (pharmaceutical) composition of thepresent invention) is selected from a range of about 5:1 (w/w) to about1:10 (w/w), more preferably from a range of about 4:1 (w/w) to about 1:8(w/w), even more preferably from a range of about 3:1 (w/w) to about 1:5(w/w) or 1:3 (w/w), and most preferably the ratio of complexed mRNA tofree mRNA in the inventive pharmaceutical composition is selected from aratio of about 1:1 (w/w).

The complexed RNA in the (pharmaceutical) composition according to thepresent invention, is preferably prepared according to a first step bycomplexing the RNA according to the invention with a cationic orpolycationic compound and/or with a polymeric carrier, preferably asdefined herein, in a specific ratio to form a stable complex. In thiscontext, it is highly preferable, that no free cationic or polycationiccompound or polymeric carrier or only a negligibly small amount thereofremains in the component of the complexed RNA after complexing the RNA.Accordingly, the ratio of the RNA and the cationic or polycationiccompound and/or the polymeric carrier in the component of the complexedRNA is typically selected in a range so that the RNA is entirelycomplexed and no free cationic or polycationic compound or polymericcarrier or only a negligibly small amount thereof remains in thecomposition.

Preferably the ratio of the RNA as defined herein to the cationic orpolycationic compound and/or the polymeric carrier, preferably asdefined herein, is selected from a range of about 5:1 (w/w) to about0,25:1 (w/w), more preferably from about 5:1 (w/w) to about 0.5:1 (w/w),even more preferably of about 4:1 (w/w) to about 1:1(w/w) or of about3:1 (w/w) to about 1:1(w/w), and most preferably a ratio of about 3:1(w/w) to about 2:1 (w/w). Alternatively, the ratio of the RNA as definedherein to the cationic or polycationic compound and/or the polymericcarrier, preferably as defined herein, in the component of the complexedmRNA, may also be calculated on the basis of the nitrogen/phosphateratio (N/P-ratio) of the entire complex. In the context of the presentinvention, an N/P-ratio is preferably in the range of about 0.1 to 10,preferably in a range of about 0.3 to 4 and most preferably in a rangeof about 0.5 to 2 or 0.7 to 2 regarding the ratio of RNA : cationic orpolycationic compound and/or polymeric carrier, preferably as definedherein, in the complex, and most preferably in a range of about 0.7 to1.5, 0.5 to 1 or 0.7 to 1, and even most preferably in a range of about0.3 to 0.9 or 0.5 to 0.9, preferably provided that the cationic orpolycationic compound in the complex is a cationic or polycationiccationic or polycationic protein or peptide and/or the polymeric carrieras defined above.

In other embodiments, the composition according to the inventioncomprising the RNA as defined herein may be administered naked withoutbeing associated with any further vehicle, transfection or complexationagent.

It has to be understood and recognized, that according to the presentinvention, the inventive composition may comprise at least one naked RNAas defined herein, preferably an mRNA, and/or at least oneformulated/complexed RNA as defined herein, preferably an mRNA, whereinevery formulation and/or complexation as disclosed above may be used.

In embodiments, wherein the (pharmaceutical) composition comprises morethan one RNA species, these RNA species may be provided such that, forexample, two, three, four, five or six separate compositions, which maycontain at least one RNA species each (e.g. three distinct mRNAspecies), each encoding distinct therapeutic proteins as defined hereinor a fragment or variant thereof as, are provided, which may or may notbe combined. Also, the (pharmaceutical) composition may be a combinationof at least two distinct compositions, each composition comprising atleast one mRNA encoding at least one of the therapeutic proteins definedherein. Alternatively, the (pharmaceutical) composition may be providedas a combination of at least one mRNA, preferably at least two, three,four, five, six or more mRNAs, each encoding one of the therapeuticproteins defined herein. The (pharmaceutical) composition may becombined to provide one single composition prior to its use or it may beused such that more than one administration is required to administerthe distinct mRNA species encoding a certain combination of the proteinsas defined herein. If the (pharmaceutical) composition contains at leastone mRNA molecule, typically at least two mRNA molecules, encoding of acombination of therapeutic proteins defined herein, it may e.g. beadministered by one single administration (combining all mRNA species),by at least two separate administrations. Accordingly; any combinationof mono-, bi- or multicistronic mRNAs encoding the at least onetherapeutic protein or any combination of therapeutic proteins asdefined herein (and optionally further proteins), provided as separateentities (containing one mRNA species) or as combined entity (containingmore than one mRNA species), is understood as a (pharmaceutical)composition according to the present invention. According to aparticularly preferred embodiment of the (pharmaceutical) composition,the at least one therapeutic protein, preferably a combination of atleast two, three, four, five, six or more therapeutic proteins encodedby the (pharmaceutical) composition as a whole, is provided as anindividual (monocistronic) mRNA, which is administered separately.

The (pharmaceutical) composition according to the present invention maybe provided in liquid and or in dry (e.g. lyophilized) form.

The (pharmaceutical) composition typically comprises a safe andeffective amount of the RNA according to the invention as definedherein, encoding a therapeutic protein as defined herein or a fragmentor variant thereof or a combination of therapeutic proteins, preferablyas defined herein. As used herein, “safe and effective amount” means anamount of the RNA that is sufficient to significantly induce a positivemodification of a disease or disorder as defined herein. At the sametime, however, a “safe and effective amount” is small enough to avoidserious side-effects, that is to say to permit a sensible relationshipbetween advantage and risk. The determination of these limits typicallylies within the scope of sensible medical judgment. In relation to the(pharmaceutical) composition of the present invention, the expression“safe and effective amount” preferably means an amount of the RNA (andthus of the encoded therapeutic protein) that is suitable for obtainingan appropriate expression level of the encoded protein(s). Such a “safeand effective amount” of the RNA of the (pharmaceutical) composition asdefined herein may furthermore be selected in dependence of the type ofRNA, e.g. monocistronic, bi- or even multicistronic RNA, since a bi- oreven multicistronic RNA may lead to a significantly higher expression ofthe encoded protein(s) than the use of an equal amount of amonocistronic RNA. A “safe and effective amount” of the RNA of the(pharmaceutical) composition as defined above will furthermore vary inconnection with the particular condition to be treated and also with theage and physical condition of the patient to be treated, the severity ofthe condition, the duration of the treatment, the nature of theaccompanying therapy, of the particular pharmaceutically acceptablecarrier used, and similar factors, within the knowledge and experienceof the accompanying doctor. The (pharmaceutical) composition accordingto the invention can be used according to the invention for human andalso for veterinary medical purposes.

In a preferred embodiment, the RNA of the (pharmaceutical) compositionor kit of parts according to the invention is provided in lyophilizedform. Preferably, the lyophilized RNA is reconstituted in a suitablebuffer, advantageously based on an aqueous carrier, prior toadministration, e.g. Ringer-Lactate solution, which is preferred, Ringersolution, a phosphate buffer solution. In a preferred embodiment, the(pharmaceutical) composition or the kit of parts according to theinvention contains at least two, three, four, five, six or more RNAs,preferably mRNAs which are provided separately in lyophilized form(optionally together with at least one further additive) and which arepreferably reconstituted separately in a suitable buffer (such asRinger-Lactate solution) prior to their use so as to allow individualadministration of each of the (monocistronic) RNAs.

The (pharmaceutical) composition according to the invention maytypically contain a pharmaceutically acceptable carrier. The expression“pharmaceutically acceptable carrier” as used herein preferably includesthe liquid or non-liquid basis of the composition. If the composition isprovided in liquid form, the carrier will be water, typicallypyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.gphosphate, citrate etc. buffered solutions. Particularly for injectionof the (pharmaceutical) composition, water or preferably a buffer, morepreferably an aqueous buffer, may be used, containing a sodium salt,preferably at least 50 mM of a sodium salt, a calcium salt, preferablyat least 0,01 mM of a calcium salt, and optionally a potassium salt,preferably at least 3 mM of a potassium salt. According to a preferredembodiment, the sodium, calcium and, optionally, potassium salts mayoccur in the form of their halogenides, e.g. chlorides, iodides, orbromides, in the form of their hydroxides, carbonates, hydrogencarbonates, or sulfates, etc. Without being limited thereto, examples ofsodium salts include e.g. NaCl, NaI, NaBr, Na₂CO₃, NaHCO₃, Na₂SO₄,examples of the optional potassium salts include e.g. KCl, KI, KBr,K₂CO₃, KHCO₃, K₂SO₄, and examples of calcium salts include e.g. CaCl₂,CaI₂, CaBr₂, CaCO₃, CaSO₄, Ca(OH)₂. Furthermore, organic anions of theaforementioned cations may be contained in the buffer. According to amore preferred embodiment, the buffer suitable for injection purposes asdefined above, may contain salts selected from sodium chloride (NaCl),calcium chloride (CaCl₂) and optionally potassium chloride (KCl),wherein further anions may be present additional to the chlorides. CaCl₂can also be replaced by another salt like KCl. Typically, the salts inthe injection buffer are present in a concentration of at least 50 mMsodium chloride (NaCl), at least 3 mM potassium chloride (KCl) and atleast 0,01 mM calcium chloride (CaCl₂). The injection buffer may behypertonic, isotonic or hypotonic with reference to the specificreference medium, i.e. the buffer may have a higher, identical or lowersalt content with reference to the specific reference medium, whereinpreferably such concentrations of the afore mentioned salts may be used,which do not lead to damage of cells due to osmosis or otherconcentration effects. Reference media are e.g. in “in vivo” methodsoccurring liquids such as blood, lymph, cytosolic liquids, or other bodyliquids, or e.g. liquids, which may be used as reference media in “invitro” methods, such as common buffers or liquids. Such common buffersor liquids are known to a skilled person. Ringer-Lactate solution isparticularly preferred as a liquid basis.

However, one or more compatible solid or liquid fillers or diluents orencapsulating compounds may be used as well, which are suitable foradministration to a person. The term “compatible” as used herein meansthat the constituents of the composition according to the invention arecapable of being mixed with the RNA according to the invention asdefined herein, in such a manner that no interaction occurs, which wouldsubstantially reduce the pharmaceutical effectiveness of the(pharmaceutical) composition according to the invention under typicaluse conditions. Pharmaceutically acceptable carriers, fillers anddiluents must, of course, have sufficiently high purity and sufficientlylow toxicity to make them suitable for administration to a person to betreated. Some examples of compounds which can be used aspharmaceutically acceptable carriers, fillers or constituents thereofare sugars, such as, for example, lactose, glucose, trehalose andsucrose; starches, such as, for example, corn starch or potato starch;dextrose; cellulose and its derivatives, such as, for example, sodiumcarboxymethylcellulose, ethylcellulose, cellulose acetate; powderedtragacanth; malt; gelatin; tallow; solid glidants, such as, for example,stearic acid, magnesium stearate; calcium sulfate; vegetable oils, suchas, for example, groundnut oil, cottonseed oil, sesame oil, olive oil,corn oil and oil from theobroma; polyols, such as, for example,polypropylene glycol, glycerol, sorbitol, mannitol and polyethyleneglycol; alginic acid.

The choice of a pharmaceutically acceptable carrier is determined, inprinciple, by the manner, in which the pharmaceutical compositionaccording to the invention is administered. The (pharmaceutical)composition can be administered, for example, systemically or locally.Routes for systemic administration in general include, for example,transdermal, oral, parenteral routes, including subcutaneous,intravenous, intramuscular, intraarterial, intradermal andintraperitoneal injections and/or intranasal administration routes.Routes for local administration in general include, for example, topicaladministration routes but also intradermal, transdermal, subcutaneous,or intramuscular injections or intralesional, intracranial,intrapulmonal, intracardial, and sublingual injections. More preferably,the (pharmaceutical) composition according to the present invention maybe administered by an intradermal, subcutaneous, or intramuscular route,preferably by injection, which may be needle-free and/or needleinjection. The (pharmaceutical) composition is therefore preferablyformulated in liquid or solid form. The suitable amount of the(pharmaceutical) composition according to the invention to beadministered can be determined by routine experiments, e.g. by usinganimal models. Such models include, without implying any limitation,rabbit, sheep, mouse, rat, dog and non-human primate models. Preferredunit dose forms for injection include sterile solutions of water,physiological saline or mixtures thereof. The pH of such solutionsshould be adjusted to about 7.4. Suitable carriers for injection includehydrogels, devices for controlled or delayed release, polylactic acidand collagen matrices. Suitable pharmaceutically acceptable carriers fortopical application include those which are suitable for use in lotions,creams, gels and the like. If the (pharmaceutical) composition is to beadministered perorally, tablets, capsules and the like are the preferredunit dose form. The pharmaceutically acceptable carriers for thepreparation of unit dose forms which can be used for oral administrationare well known in the prior art. The choice thereof will depend onsecondary considerations such as taste, costs and storability, which arenot critical for the purposes of the present invention, and can be madewithout difficulty by a person skilled in the art.

Further additives which may be included in the (pharmaceutical)composition are emulsifiers, such as, for example, Tween; wettingagents, such as, for example, sodium lauryl sulfate; colouring agents;taste-imparting agents, pharmaceutical carriers; tablet-forming agents;stabilizers; antioxidants; preservatives.

The (pharmaceutical) composition as defined herein may also beadministered orally in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions.

The (pharmaceutical) composition may also be administered topically,especially when the target of treatment includes areas or organs readilyaccessible by topical application, e.g. including diseases of the skinor of any other accessible epithelial tissue. Suitable topicalformulations are readily prepared for each of these areas or organs. Fortopical applications, the (pharmaceutical) composition may be formulatedin a suitable ointment, containing the RNA according to the inventionsuspended or dissolved in one or more carriers.

According to a preferred embodiment of this aspect of the invention, the(pharmaceutical) composition according to the invention is administeredby injection. Any suitable injection technique known in the art may beemployed. Preferably, the inventive composition is administered byinjection, preferably by needle-less injection, for example byjet-injection.

In one embodiment, the (pharmaceutical) composition comprises at leasttwo, three, four, five, six, seven, eight, nine, ten, eleven, twelve ormore RNAs as defined herein, each of which is preferably injectedseparately, preferably by needle-less injection. Alternatively, the(pharmaceutical) composition comprises at least two, three, four, five,six, seven, eight, nine, ten, eleven, twelve or more RNAs, wherein theat least two, three, four, five, six, seven, eight, nine, ten, eleven,twelve or more RNAs are administered, preferably by injection as definedherein, as a mixture.

Administration of the RNA as defined herein or the (pharmaceutical)composition according to the invention may be carried out in a timestaggered treatment. A time staggered treatment may be e.g.administration of the RNA or the composition prior, concurrent and/orsubsequent to a conventional therapy of a disease or disorder,preferably as described herein, e.g. by administration of the RNA or thecomposition prior, concurrent and/or subsequent to a therapy or anadministration of a therapeutic agent suitable for the treatment orprophylaxis of a disease or disorder as described herein. Such timestaggered treatment may be carried out using e.g. a kit, preferably akit of parts as defined herein.

Time staggered treatment may additionally or alternatively also comprisean administration of the RNA as defined herein or the (pharmaceutical)composition according to the invention in a form, wherein the RNAencoding a therapeutic protein as defined herein or a fragment orvariant thereof, preferably forming part of the composition, isadministered parallel, prior or subsequent to another RNA encoding atherapeutic protein as defined above, preferably forming part of thesame inventive composition. Preferably, the administration (of all RNAs)occurs within an hour, more preferably within 30 minutes, even morepreferably within 15, 10, 5, 4, 3, or 2 minutes or even within 1 minute.Such time staggered treatment may be carried out using e.g. a kit,preferably a kit of parts as defined herein.

The present invention furthermore provides several applications and usesof the RNA, of the (pharmaceutical) composition or the kit of partsaccording to the invention.

According to a further aspect, the present invention also provides amethod for increasing the expression of an encoded peptide or proteincomprising the steps, e.g. a) providing the RNA as defined herein or the(pharmaceutical) composition as defined herein, b) applying oradministering the RNA or the composition to an expression system, e.g.to a cell-free expression system, a cell (e.g. an expression host cellor a somatic cell), a tissue or an organism. The method may be appliedfor laboratory, for research, for diagnostic, for commercial productionof peptides or proteins and/or for therapeutic purposes. In thiscontext, typically after preparing the RNA or the composition, it istypically applied or administered to a cell-free expression system, acell (e.g. an expression host cell or a somatic cell), a tissue or anorganism, e.g. in naked or complexed form or as a (pharmaceutical)composition as described herein, preferably via transfection or by usingany of the administration modes as described herein. The method may becarried out in vitro, in viva or ex viva. The method may furthermore becarried out in the context of the treatment of a specific disease,preferably as defined herein.

In this context is vitro is defined herein as transfection ortransduction of the RNA or the composition according to the inventioninto cells in culture outside of an organism; is vivo is defined hereinas transfection or transduction of the RNA or the composition accordingto the invention into cells by application of the RNA or the compositionto the whole organism or individual and ex viva is defined herein astransfection or transduction of the RNA or the composition according tothe invention into cells outside of an organism or individual andsubsequent application of the transfected cells to the organism orindividual.

Likewise, according to another aspect, the present invention alsoprovides the use of the RNA or the composition according to theinvention, preferably for diagnostic or therapeutic purposes, forincreasing the expression of an encoded peptide or protein, particularlyin gene therapy e.g. by applying or administering the RNA or thecomposition, e.g. to a cell-free expression system, a cell (e.g. anexpression host cell or a somatic cell), a tissue or an organism. Theuse may be applied for laboratory, for research, for diagnostic forcommercial production of peptides or proteins and/or for therapeuticpurposes, preferably for gene therapy. In this context, typically afterpreparing the RNA or the composition according to the invention, it istypically applied or administered to a cell-free expression system, acell (e.g. an expression host cell or a somatic cell), a tissue or anorganism, preferably in naked form or complexed form, or as a(pharmaceutical) composition as described herein, preferably viatransfection or by using any of the administration modes as describedherein. The use may be carried out in vitro, in vivo or ex viva. The usemay furthermore be carried out in the context of the treatment orprevention of a specific disease, preferably as defined herein. Morepreferably, the use is carried out in gene therapy in a disease,disorder or condition amenable to treatment by (increasing the)expression of the peptide or protein that is encoded by the at least onecoding sequence of the RNA according to the invention. Even morepreferably, the use is carried out in gene therapy in a disease,disorder or condition indicated in Tablet i.e. indicated under featurec5, preferably for the encoded peptide or protein.

In the context of the present invention, the expression “disease,disorder or condition amenable to treatment by (increasing the)expression of the peptide or protein that is encoded by the at least onecoding sequence of the RNA” typically refers to any disease, disorder orcondition, which may be positively influenced (e.g. cured, amelioratedor prevented) by expressing a therapeutic protein as defined herein (orincreasing the expression thereof), e.g. by administration of the RNAaccording to the invention.

As used herein, the expression “a disease, disorder or conditionindicated in Table 1” typically relates to any diseases, disorder orcondition specified in feature c5 of Table 1. Preferably, a certaintherapeutic protein as defined herein, preferably a therapeutic proteinselected from the peptides or proteins specified in Table 1 is used inconnection with a disease, disorder or condition as indicated in featurec5 of the respective entry in Table 1.

In yet another aspect the present invention also relates to an inventiveexpression system comprising the RNA according to the invention or anexpression vector or plasmid comprising a corresponding nucleic acidsequence according to the first aspect of the present invention. In thiscontext the expression system may be a cell-free expression system (e.g.an is vitro transcription/translation system), a cellular expressionsystem (e.g. mammalian cells like CHO cells, insect cells, yeast cells,bacterial cells like E.coli) or organisms used for expression ofpeptides or proteins (e.g. plants or animals like cows).

According to one specific aspect, the present invention is directed tothe first medical use of the RNA according to the invention or of the(pharmaceutical) composition comprising the RNA according to theinvention or a plurality of inventive RNAs as defined herein as amedicament, particularly in gene therapy, preferably for the treatmentor prevention of diseases as defined herein.

According to another aspect, the present invention is directed to thesecond medical use of the RNA according to the invention or of the(pharmaceutical) composition comprising the RNA according to theinvention or a plurality of inventive RNAs as defined herein, for thetreatment or prevention of diseases as defined herein, preferably to theuse of the RNA as defined herein, of the (pharmaceutical) composition asdefined herein, of a pharmaceutical composition comprising same or ofkits comprising same for the preparation of a medicament for theprophylaxis, treatment and/or amelioration of diseases as definedherein. Preferably, the pharmaceutical composition is used on or to beadministered to a patient in need thereof for this purpose.

According to a further aspect, the RNA according to the invention isused in the manufacture of a medicament, wherein the medicament ispreferably for treatment or prophylaxis of a disease or disorder asdefined herein.

According to a preferred embodiment, a disease or disorder in thecontext of the present invention is a disease, disorder or conditionamenable to treatment by (increasing the) expression of the peptide orprotein encoded by the at least one coding sequence.

Preferably, diseases as mentioned herein are preferably selected frominfectious diseases, neoplasms (e.g. cancer or tumour diseases),diseases of the blood and blood-forming organs, endocrine, nutritionaland metabolic diseases, diseases of the nervous system, diseases of thecirculatory system, diseases of the respiratory system, diseases of thedigestive system, diseases of the skin and subcutaneous tissue, diseasesof the musculoskeletal system and connective tissue, and diseases of thegenitourinary system.

In this context particularly preferred are inherited diseases selectedfrom: Ip36 deletion syndrome; 18p deletion syndrome; 21-hydroxylasedeficiency; 45,X (Turner syndrome); 47,XX,+21 (Down syndrome); 47,XXX(triple X syndrome); 47,XXY (Klinefelter syndrome); 47,XY,+21 (Downsyndrome); 47,XYY syndrome; 5-ALA dehydratase-deficient porphyria (ALAdehydratase deficiency); 5-aminolaevulinic dehydratase deficiencyporphyria (ALA dehydratase deficiency); 5p deletion syndrome (Cri duchat) 5p-syndrome (Cri du chat); A-T (ataxia-telangiectasia); AAT(alpha-1 antitrypsin deficiency); Absence of vas deferens (congenitalbilateral absence of vas deferens); Absent vasa (congenital bilateralabsence of vas deferens); aceruloplasminemia; ACG2 (achondrogenesis typeII); AH (achondroplasia); Achondrogenesis type II; achondroplasia; Acidbeth-glucosidase deficiency (Gaucher disease type 1);Acrocephalosyndactyly (Apert) (Apert syndrome); acrocephalosyndactyly,type V (Pfeiffer syndrome); Acrocephaly (Apert syndrome); Acute cerebralGaucher's disease (Gaucher disease type 2); acute intermittentporphyria; ACY2 deficiency (Canavan disease); AD (Alzheimer's disease);Adelaide-type craniosynostosis (Muenke syndrome); Adenomatous PolyposisColi (familial adenomatous polyposis); Adenomatous Polyposis of theColon (familial adenomatous polyposis); ADP (ALA dehydratasedeficiency); adenylosuccinate lyase deficiency; Adrenal gland disorders(21-hydroxylase deficiency); Adrenogenital syndrome (21-hydroxylasedeficiency); Adrenoleukodystrophy; AIP (acute intermittent porphyria);AIS (androgen insensitivity syndrome); AKU (alkaptonuria); ALAdehydratase porphyria (ALA dehydratase deficiency); ALA-D porphyria (ALAdehydratase deficiency); ALA dehydratase deficiency; Alcaptonuria(alkaptonuria); Alexander disease; alkaptonuria; Alkaptonuric ochronosis(alkaptonuria); alpha-1 antitrypsin deficiency; alpha-1 proteinaseinhibitor (alpha-1 antitrypsin deficiency); alpha-1 related emphysema(alpha-1 antitrypsin deficiency); Alpha-galactosidase A deficiency(Fabry disease); ALS (amyotrophic lateral sclerosis); Alstrom syndrome;ALX (Alexander disease); Alzheimer disease; Amelogenesis Imperfecta;Amino levulinic acid dehydratase deficiency (ALA dehydratasedeficiency); Aminoacylase 2 deficiency (Canavan disease); amyotrophiclateral sclerosis; Anderson-Fabry disease (Fabry disease); androgeninsensitivity syndrome; Anemia; Anemia, hereditary sideroblastic(X-linked sideroblastic anemia); Anemia, sex-linked hypochromicsideroblastic (X-linked sideroblastic anemia); Anemia, splenic, familial(Geuther disease); Angelman syndrome; Angiokeratoma Corporis Diffusum(Fabry's disease); Angiokeratoma diffuse (Fabry's disease); Angiomatosisretinae (von Hippel-Lindau disease); ANHI (X-linked sideroblasticanemia); APC resistance, Leiden type (factor V Leiden thrombophilia);Apert syndrome; AR deficiency (androgen insensitivity syndrome); AR-CMT2ee (Charcot-Mare-Tooth disease, type 2); Arachnodactyly (Marfansyndrome); ARNSHL (Nonsyndromic deafness #autosomal recessive);Arthro-ophthalmopathy, hereditary progressive (Stickler syndrome#COL2A1); Arthrochalasis multiplex congenita (Ehlers-Danlossyndrome#arthrochalasia type); AS (Angelman syndrome); Asp deficiency(Canavan disease); Asp deficiency (Canavan disease); Aspartoacylasedeficiency (Canavan disease); ataxia-telangiectasia;Autism-Dementia-Ataxia-Loss of Purposeful Hand Use syndrome (Rettsyndrome); autosomal dominant juvenile ALS (amyotrophic lateralsclerosis, type 4); Autosomal dominant opitz G/BBB syndrome (22q11.2deletion syndrome); autosomal recessive form of juvenile ALS type 3(Amyotrophic lateral sclerosis #type 2); Autosomal recessivenonsyndromic hearing loss (Nonsyndromic deafness #autosomal recessive);Autosomal Recessive Sensorineural Hearing Impairment and Goiter (Pendredsyndrome); AxD (Alexander disease); Ayerza syndrome (primary pulmonaryhypertension); B variant of the Hexosaminidase GM2 gangliosidosis(Sandhoff disease); BANF (neurofibromatosis 2); Beare-Stevenson cubsgyrate syndrome; Benign paroxysmal peritonitis (Mediterranean fever,familial); Benjamin syndrome; beta thalassemia; BH4 Deficiency(tetrahydrobiopterin deficiency); Bilateral Acoustic Neurofibromatosis(neurofibromatosis 2); biotinidase deficiency; bladder cancer; Bleedingdisorders (factor V Leiden thrombophilia); Bloch-Sulzberger syndrome(incontinentia pigmenti); Bloom syndrome; Bone diseases; Bone marrowdiseases (X-linked sideroblastic anemia); Bonnevie-Ullrich syndrome(Turner syndrome); Bourneville disease (tuberous sclerosis); Bournevillephakomatosis (tuberous sclerosis); Brain diseases (prion disease);breast cancer; Birt-Hogg-Dube syndrome; Brittle bone disease(osteogenesis imperfecta); Broad Thumb-Hallux syndrome (Rubinstein-Taybisyndrome); Bronze Diabetes (hemochromatosis); Bronzed cirrhosis(hemochromatosis); Bulbospinal muscular atrophy, X-linked (Kennedydisease); Burger-Grutz syndrome (lipoprotein lipase deficiency,familial); CADASIL; CGD Chronic Granulomatous Disorder; Camptomelicdysplasia; Canavan disease; Cancer; Cancer Family syndrome (hereditarynonpolyposis colorectal cancer); Cancer of breast (breast cancer);Cancer of the bladder (bladder cancer); Carboxylase Deficiency,Multiple, Late-Onset (biotinidase deficiency); Cardiomyopathy (Noonansyndrome); Cat cry syndrome (Cri du chat); CAVD (congenital bilateralabsence of vas deferens); Caylor cardiofacial syndrome (22q11.2 deletionsyndrome); CBAVD (congenital bilateral absence of vas deferens); CeliacDisease; CEP (congenital erythropoietic porphyria); Ceramidetrihexosidase deficiency (Fabry disease); Cerebelloretinal Angiomatosis,familial (von Hippel-Lindau disease); Cerebral arteriopathy withsubcortical infarcts and leukoencephalopathy (CADASIL); Cerebralautosomal dominant ateriopathy with subcortical infarcts andleukoencephalopathy (CADASIL); Cerebral sclerosis (tuberous sclerosis);Cerebroatrophic Hyperammonemia (Rett syndrome); Cerebroside Lipidosissyndrome (Gaucher disease); CF (cystic fibrosis); H (congenitalhypothyroidism); Cheroot disease (amyotrophic lateral sclerosis);Charcot-Marie-Tooth disease; Chondrodystrophia (achondroplasia);Chondrodystrophy syndrome (achondroplasia); Chondrodystrophy withsensorineural deafness (otospondylomegaepiphyseal dysplasia);Chondrogenesis imperfecta (achondrogenesis, type II); Choreoathetosisself-mutilation hyperuricemia syndrome (Lesch-Nyhan syndrome); ClassicGalactosemia (galactosemia); Classical Ehlers-Danlos syndrome(Ehlers-Danlos syndrome #classical type); Classical Phenylketonuria(phenylketonuria); Cleft lip and plate (Stickler syndrome); Cloverleafskull with thanatophoric dwarfism (Thanatophoric dysplasia #type 2); CLS(Coffin-Lowry syndrome); CMT (Charcot-Marie-Tooth disease); Cockaynesyndrome; Coffin-Lowry syndrome; collagenopathy, types II and XI; ColonCancer, familial Nonpolyposis (hereditary nonpolyposis colorectalcancer); Colon cancer, familial (familial adenomatous polyposis);Colorectal Cancer; Complete HPRT deficiency (Lesch-Nyhan syndrome);Complete hypoxanthine-guanine phosphoribosy transferase deficiency(Lesch-Nyhan syndrome); Compression neuropathy (hereditary neuropathywith liability to pressure palsies); Congenital adrenal hyperplasia(21-hydroxylase deficiency); congenital bilateral absence of vasdeferens (Congenital absence of the vas deferens); Congenitalerythropoietic porphyria; Congenital heart disease; Congenitalhypomyelination (Charcot-Marie-Tooth disease #Type 1/Charcot-Marie-Toothdisease #Type 4); Congenital hypothyroidism; Congenitalmethemoglobinemia (Methemoglobinemia #Congenital methaemoglobinaemia);Congenital osteosclerosis (achondroplasia); Congenital sideroblasticanaemia (X-linked sideroblastic anemia); Connective tissue disease;Conotruncal anomaly face syndrome (22q11.2 deletion syndrome); Cooley'sAnemia (beta thalassemia); Copper storage disease (Wilson disease);Copper transport disease (Menkes disease); Coproporphyria, hereditary(hereditary coproporphyria); Coproporphyrinogen oxidase deficiency(hereditary coproporphyria); Cowden syndrome; CPO deficiency (hereditarycoproporphyria); CPRO deficiency (hereditary coproporphyria); CPXdeficiency (hereditary coproporphyria); Craniofacial dysarthrosis(Crouzon syndrome); Craniofacial Dysostosis (Crouzon syndrome);Cretinism (congenital hypothyroidism); Creutzfeldt-Jakob disease (priondisease); Cri du chat (Crohn's disease, fibrostenosing); Crouzonsyndrome; Crouzon syndrome with acanthosis nigricans(Crouzonodermoskeletal syndrome); Crouzonodermoskeletal syndrome; CS(Cockayne syndrome)(Cowden syndrome); Curschmann-Batten-Steinertsyndrome (myotonic dystrophy); cubs gyrata syndrome of Beare-Stevenson(Beare-Stevenson cubs gyrata syndrome); Disorder Mutation Chromosome;D-glycerite dehydrogenase deficiency (hyperoxaluria, primary); Dappledmetaphysis syndrome (spondyloepimetaphyseal dysplasia, Strudwick type);DAT—Dementia Alzheimer's type (Alzheimer disease); Genetichypercalciuria (Dent's disease); DBMD (muscular dystrophy, Duchenne andBecker types); Deafness with goiter (Pendred syndrome);Deafness-retinitis pigmentosa syndrome (Usher syndrome); Deficiencydisease, Phenylalanine Hydroxylase (phenylketonuria); Degenerative nervediseases; de Grouchy syndrome 1 (De Grouchy Syndrome); Dejerine-Sottassyndrome (Charcot-Marie-Tooth disease); Delta-aminolevulinatedehydratase deficiency porphyria (ALA dehydratase deficiency); Dementia(CADASIL); demyelinogenic leukodystrophy (Alexander disease);Dermatosparactic type of Ehlers-Danlos syndrome (Ehlers-Danlos syndrome#dermatosparaxis type); Dermatosparaxis (Ehlers-Danlos syndrome#dermatosparaxis type) ; developmental disabilities; dHMN (Amyotrophiclateral sclerosis #type 4); DHMN-V (distal spinal muscular atrophy, typeV); DHTR deficiency (androgen insensitivity syndrome); Diffuse GloboidBody Sclerosis (Krabbe disease); DiGeorge syndrome; Dihydrotestosteronereceptor deficiency (androgen insensitivity syndrome); distal spinalmuscular atrophy, type V; DM1 (Myotonic dystrophy #type1); DM2 (Myotonicdystrophy #type2); Down syndrome; DSMAV (distal spinal muscular atrophy,type V); DSN (Charcot-Marie-Tooth disease #type 4); DSS(Charcot-Marie-Tooth disease, type 4); Duchenne/Becker musculardystrophy (muscular dystrophy, Duchenne and Becker types); Dwarf,achondroplastic (achondroplasia); Dwarf, thanatophoric (thanatophoricdysplasia); Dwarfism; Dwarfism-retinal atrophy-deafness syndrome(Cockayne syndrome); dysmyelinogenic leukodystrophy (Alexander disease);Dystrophia myotonica (myotonic dystrophy); dystrophia retinaepigmentosa-dysostosis syndrome (Usher syndrome); Early-Onset familialalzheimer disease (EDFAD) (Alzheimer disease); EDS (Ehlers-Danlossyndrome); Ehlers-Danlos syndrome; Ekman-Lobstein disease (osteogenesisimperfecta); Entrapment neuropathy (hereditary neuropathy with liabilityto pressure palsies); Epiloia (tuberous sclerosis); EPP (erythropoieticprotoporphyria); Erythroblastic anemia (beta thalassemia);Erythrohepatic protoporphyria (erythropoietic protoporphyria); Erythroid5-aminolevulinate synthetase deficiency (X-linked sideroblastic anemia);Erythropoietic porphyria (congenital erythropoietic porphyria);Erythropoietic protoporphyria; Erythropoietic uroporphyrin (congenitalerythropoietic porphyria); Eye cancer (retinoblastoma FA—Friedreichataxia); Fabry disease; Facial injuries and disorders; Factor V Leidenthrombophilia; FALS (amyotrophic lateral sclerosis); familial acousticneuroma (neurofibromatosis type II); familial adenomatous polyposis;familial Alzheimer disease (FAD) (Alzheimer disease); familialamyotrophic lateral sclerosis (amyotrophic lateral sclerosis); familialdysautonomia; familial fat-induced hypertriglyceridemia (lipoproteinlipase deficiency, familial); familial hemochromatosis(hemochromatosis); familial LPL deficiency (lipoprotein lipasedeficiency, familial); familial nonpolyposis colon cancer (hereditarynonpolyposis colorectal cancer); familial paroxysmal polyserositis(Mediterranean fever, familial); familial PET (porphyria cutanea tarda);familial pressure sensitive neuropathy (hereditary neuropathy withliability to pressure palsies); familial primary pulmonary hypertension(FPPH) (primary pulmonary hypertension); Familial Turner syndrome(Noonan syndrome); familial vascular leukoencephalopathy (CADASIL); FAP(familial adenomatous polyposis); FD (familial dysautonomia); Femalepseudo-Turner syndrome (Noonan syndrome); Ferrochelatase deficiency(erythropoietic protoporphyria); ferroportin disease (Haemochromatosis#type 4); Fever (Mediterranean fever, familial); FG syndrome;FGFR3-associated coronal synostosis (Muenke syndrome); Fibrinoiddegeneration of astrocytes (Alexander disease); Fibrocystic disease ofthe pancreas (cystic fibrosis); FMF (Mediterranean fever, familial);Folling disease (phenylketonuria); fra(X) syndrome (fragile X syndrome);fragile X syndrome; Fragilitas ossium (osteogenesis imperfecta); FRAXAsyndrome (fragile X syndrome); FRDA (Friedreich's ataxia); Friedreichataxia (Friedreich's ataxia); Friedreich's ataxia; FXS (fragile Xsyndrome); GBPD deficiency; Galactokinase deficiency disease(galactosemia); Galactose-1-phosphate uridyl-transferase deficiencydisease (galactosemia); galactosemia; Galactosylceramidase deficiencydisease (Krabbe disease); Galactosylceramide lipidosis (Krabbe disease);galactosylcerebrosidase deficiency (Krabbe disease);galactosylsphingosine lipidosis (Krabbe disease); GALC deficiency(Krabbe disease); GALT deficiency (galactosemia); Gaucher disease;Gaucher-like disease (pseudo-Gaucher disease); GBA deficiency (Gaucherdisease type 1); GD (Gaucher's disease); Genetic brain disorders;genetic emphysema (alpha-1 antitrypsin deficiency); genetichemochromatosis (hemochromatosis); Giant cell hepatitis, neonatal(Neonatal hemochromatosis); GLA deficiency (Fabry disease);Glioblastoma, retinal (retinoblastoma); Glioma, retinal(retinoblastoma); globoid cell leukodystrophy (GEL, GLD) (Krabbedisease); globoid cell leukoencephalopathy (Krabbe disease);Glucocerebrosidase deficiency (Gaucher disease); Glucocerebrosidosis(Gaucher disease); Glucosyl cerebroside lipidosis (Gaucher disease) ;Glucosylceramidase deficiency (Gaucher disease); Glucosylceramidebeth-glucosidase deficiency (Gaucher disease); Glucosylceramidelipidosis (Gaucher disease); Glyceric aciduria (hyperoxaluria, primary);Glycine encephalopathy (Nonketotic hyperglycinemia); Glycolic aciduria(hyperoxaluria, primary); GM2 gangliosidosis, type 1 (Tay-Sachsdisease); Goiter-deafness syndrome (Pendred syndrome); Graefe-Ushersyndrome (Usher syndrome); Gronblad-Strandberg syndrome (pseudoxanthomaelasticum); Guenther porphyria (congenital erythropoietic porphyria);Gunther disease (congenital erythropoietic porphyria); Haemochromatosis(hemochromatosis); Hallgren syndrome (Usher syndrome); HarlequinIchthyosis; Hb S disease (sickle cell anemia); HCH (hypochondroplasia);HCP (hereditary coproporphyria); Head and brain malformations; Hearingdisorders and deafness; Hearing problems in children; HEF2A(hemochromatosis #type 2); HEF2B (hemochromatosis #type 2);Hematoporphyria (porphyria); Home synthetase deficiency (erythropoieticprotoporphyria); Hemochromatoses (hemochromatosis); hemochromatosis;hemoglobin M disease (methemoglobinemia #beta-globin type); Hemoglobin Sdisease (sickle cell anemia); hemophilia; HEP (hepatoerythropoieticporphyria); hepatic AGT deficiency (hyperoxaluria, primary);hepatoerythropoietic porphyria; Hepatolenticular degeneration syndrome(Wilson disease); Hereditary arthro-ophthalmopathy (Stickler syndrome);Hereditary coproporphyria; Hereditary dystopic lipidosis (Fabrydisease); Hereditary hemochromatosis (HHC) (hemochromatosis); HereditaryInclusion Body Myopathy (skeletal muscle regeneration); Hereditaryiron-loading anemia (X-linked sideroblastic anemia); Hereditary motorand sensory neuropathy (Charcot-Marie-Tooth disease); Hereditary motorneuronopathy (spinal muscular atrophy); Hereditary motor neuronopathy,type V (distal spinal muscular atrophy, type V); Hereditary MultipleExostoses; Hereditary nonpolyposis colorectal cancer; Hereditaryperiodic fever syndrome (Mediterranean fever, familial); HereditaryPolyposis Coli (familial adenomatous polyposis); Hereditary pulmonaryemphysema (alpha-1 antitrypsin deficiency); Hereditary resistance toactivated protein C (factor V Leiden thrombophilia); Hereditary sensoryand autonomic neuropathy type III (familial dysautonomia); Hereditaryspastic paraplegia (infantile-onset ascending hereditary spasticparalysis); Hereditary spinal ataxia (Friedreich ataxia); Hereditaryspinal sclerosis (Friedreich ataxia); Herrick's anemia (sickle cellanemia); Heterozygous DSMED (Weissenbacher-Zweymoller syndrome);Heterozygous otospondylomegaepiphyseal dysplasia(Weissenbacher-Zweymoller syndrome); HexA deficiency (Tay-Sachsdisease); Hexosaminidase A deficiency (Tay-Sachs disease);Hexosaminidase alpha-subunit deficiency (variant B) (Tay-Sachs disease);HFE-associated hemochromatosis (hemochromatosis); HGPS (Progeria);Hippel-Lindau disease (von Hippel-Lindau disease); HLAH(hemochromatosis); HMN V (distal spinal muscular atrophy, type V); HMSN(Charcot-Marie-Tooth disease); HNPCC (hereditary nonpolyposis colorectalcancer); HNPP (hereditary neuropathy with liability to pressurepalsies); homocystinuria; Homogentisic acid oxidase deficiency(alkaptonuria); Homogentisic acidura (alkaptonuria); Homozygousporphyria cutanea tarda (hepatoerythropoietic porphyria); HP1(hyperoxaluria, primary); HP2 (hyperoxaluria, primary); HPA(hyperphenylalaninemia); HPRT—Hypoxanthine-guaninephosphoribosyltransferase deficiency (Lesch-Nyhan syndrome); HSAN typeIII (familial dysautonomia); HSAN3 (familial dysautonomia); HSN-III(familial dysautonomia); Human dermatosparaxis (Ehlers-Danlos syndrome#dermatosparaxis type); Huntington's disease; Hutchinson-Gilfordprogeria syndrome (progeria); Hyperandrogenism, nonclassic type, due to21-hydroxylase deficiency (21-hydroxylase deficiency);Hyperchylomicronemia, familial (lipoprotein lipase deficiency,familial); hyperglycinemia with ketoacidosis and leukopenia (propionicacidemia); Hyperlipoproteinemia type I (lipoprotein lipase deficiency,familial); hyperoxaluria, primary; hyperphenylalaninaemia(hyperphenylalaninemia); hyperphenylalaninemia; Hypochondrodysplasia(hypochondroplasia); hypochondrogenesis; hypochondroplasia; Hypochromicanemia (X-linked sideroblastic anemia); Hypocupremia, congenital; Menkessyndrome); hypoxanthine phosphoribosyltransf arse (HPRT) deficiency(Lesch-Nyhan syndrome); IAHSP (infantile-onset ascending hereditaryspastic paralysis); idiopathic hemochromatosis (hemochromatosis, type3); Idiopathic neonatal hemochromatosis (hemochromatosis, neonatal);Idiopathic pulmonary hypertension (primary pulmonary hypertension);Immune system disorders (X-linked severe combined immunodeficiency);Incontinentia Pigmenti; Infantile cerebral Gaucher's disease (Gaucherdisease type 2); Infantile Geuther disease (Gaucher disease type 2);infantile-onset ascending hereditary spastic paralysis; Infertility;inherited emphysema (alpha-1 antitrypsin deficiency); Inherited humantransmissible spongiform encephalopathies (prion disease); inheritedtendency to pressure palsies (hereditary neuropathy with liability topressure palsies); Insley-Astley syndrome (otospondylomegaepiphysealdysplasia); Intermittent acute porphyria syndrome (acute intermittentporphyria); Intestinal polyposis-cutaneous pigmentation syndrome(Peutz-Jeghers syndrome); IP (incontinentia pigmenti); Iron storagedisorder (hemochromatosis); Isodicentric 15 (idic15); Isolated deafness(nonsyndromic deafness); Jackson-Weiss syndrome; JH (Haemochromatosis#type 2); Joubert syndrome; JPLS (Juvenile Primary Lateral Sclerosis);juvenile amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis#type 2); Juvenile gout, choreoathetosis, mental retardation syndrome(Lesch-Nyhan syndrome); juvenile hyperuricemia syndrome (Lesch-Nyhansyndrome); JWS (Jackson-Weiss syndrome); KD (X-linked spinal-bulbarmuscle atrophy); Kennedy disease (X-linked spinal-bulbar muscleatrophy); Kennedy spinal and bulbar muscular atrophy (X-linkedspinal-bulbar muscle atrophy); Kerasin histiocytosis (Gaucher disease);Kerasin lipoidosis (Gaucher disease); Kerasin thesaurismosis (Gaucherdisease); ketotic glycinemia (propionic acidemia); ketotichyperglycinemia (propionic acidemia); Kidney diseases (hyperoxaluria,primary); Klinefelter syndrome; Klinefelter's syndrome; Kniestdysplasia; Krabbe disease; Lacunar dementia (CADASIL); Langer-Saldinoachondrogenesis (achondrogenesis, type II); Langer-Saldino dysplasia(achondrogenesis, type II); Late-onset Alzheimer disease (Alzheimerdisease #type 2); Late-onset familial Alzheimer disease (AD2) (Alzheimerdisease #type 2); late-onset Krabbe disease (LDKD) (Krabbe disease);Learning Disorders (Learning disability); Lentiginosis, perioral(Peutz-Jeghers syndrome); Lesch-Nyhan syndrome; Leukodystrophies;leukodystrophy with Rosenthal fibers (Alexander disease);Leukodystrophy, spongiform (Canavan disease); LFS (Li-Fraumenisyndrome); Li-Fraumeni syndrome; Lipase D deficiency (lipoprotein lipasedeficiency, familial); LIPD deficiency (lipoprotein lipase deficiency,familial); Lipidosis, cerebroside (Gaucher disease); Lipidosis,ganglioside, infantile (Tay-Sachs disease); Lipoid histiocytosis(kerasin type) (Gaucher disease); lipoprotein lipase deficiency,familial; Liver diseases (galactosemia); Lou Gehrig disease (amyotrophiclateral sclerosis); Louis-Bar syndrome (ataxia-telangiectasia); Lynchsyndrome (hereditary nonpolyposis colorectal cancer); Lysyl-hydroxylasedeficiency (Ehlers-Danlos syndrome #kyphoscoliosis type); Machado-Josephdisease (Spinocerebellar ataxia #type 3); Male breast cancer (breastcancer); Male genital disorders; Male Turner syndrome (Noonan syndrome);Malignant neoplasm of breast (breast cancer); malignant tumor of breast(breast cancer); Malignant tumor of urinary bladder (bladder cancer);Mammary cancer (breast cancer); Marfan syndrome 15; Marker X syndrome(fragile X syndrome); Martin-Bell syndrome (fragile X syndrome);McCune-Albright syndrome; McLeod syndrome; MEDNIK; Mediterranean Anemia(beta thalassemia); Mediterranean fever, familial; Mega-epiphysealdwarfism (otospondylomegaepiphyseal dysplasia); Menkes syndrome (Menkessyndrome); Menkes syndrome; Mental retardation with osteocartilaginousabnormalities (Coffin-Lowry syndrome); Metabolic disorders; Metatropicdwarfism, type II (Kniest dysplasia); Metatropic dysplasia type II(Kniest dysplasia); Methemoglobinemia#beta-globin type; methylmalonicacidemia; MFS (Marfan syndrome); MHAM (Cowden syndrome); MK (Menkessyndrome); Micro syndrome; Microcephaly; MMA (methylmalonic acidemia);MNK (Menkes syndrome); Monosomy 1p36 syndrome (1p36 deletion syndrome);monosomy X (Turner syndrome); Motor neuron disease, amyotrophic lateralsclerosis (amyotrophic lateral sclerosis); Movement disorders;Mowat-Wilson syndrome; Mucopolysaccharidosis (MPS I); Mucoviscidosis(cystic fibrosis); Muenke syndrome; Multi-Infarct dementia (CADASIL);Multiple carboxylase deficiency, late-onset (biotinidase deficiency);Multiple hamartoma syndrome (Cowden syndrome); Multipleneurofibromatosis (neurofibromatosis); Muscular dystrophy; Musculardystrophy, Duchenne and Becker type; Myotonia atrophia (myotonicdystrophy); Myotonia dystrophica (myotonic dystrophy); myotonicdystrophy; Myxedema, congenital (congenital hypothyroidism);Nance-Insley syndrome (otospondylomegaepiphyseal dysplasia);Nance-Sweeney chondrodysplasia (otospondylomegaepiphyseal dysplasia);NBIA1 (pantothenate kinase-associated neurodegeneration); Neill-Dingwallsyndrome (Cockayne syndrome); Neuroblastoma, retinal (retinoblastoma);Neurodegeneration with brain iron accumulation type 1(pantothenatekinase-associated neurodegeneration); Neurofibromatosis type I;Neurofibromatosis type II; Neurologic diseases; Neuromuscular disorders;neuronopathy, distal hereditary motor, type V (Distal spinal muscularatrophy #type V); neuronopathy, distal hereditary motor, with pyramidalfeatures (Amyotrophic lateral sclerosis #type 4); NF(neurofibromatosis); Niemann-Pick (Niemann-Pick disease); Noack syndrome(Pfeiffer syndrome); Nonketotic hyperglycinemia (Glycineencephalopathy); Non-neuronopathic Gaucher disease (Gaucher disease type1); Non-phenylketonuric hyperphenylalaninemia (tetrahydrobiopterindeficiency); nonsyndromic deafness; Noonan syndrome; NorrbottnianGaucher disease (Gaucher disease type 3); Dchronosis (alkaptonuria);Dchronotic arthritis (alkaptonuria); OI (osteogenesis imperfecta); DSMED(otospondylomegaepiphyseal dysplasia); osteogenesis imperfecta;Osteopsathyrosis (osteogenesis imperfecta); Osteosclerosis congenita(achondroplasia); Oto-spondylo-megaepiphyseal dysplasia(otospondylomegaepiphyseal dysplasia); otospondylomegaepiphysealdysplasia; Oxalosis (hyperoxaluria, primary); Oxaluria, primary(hyperoxaluria, primary); pantothenate kinase-associatedneurodegeneration; Patau Syndrome (Trisomy 13); PBGD deficiency (acuteintermittent porphyria); PCC deficiency (propionic acidemia); PCT(porphyria cutanea tarda); PDM (Myotonic dystrophy #type 2); Pendredsyndrome; Periodic disease (Mediterranean fever, familial); Periodicperitonitis (Mediterranean fever, familial); Periorificial lentiginosissyndrome (Peutz-Jeghers syndrome); Peripheral nerve disorders (familialdysautonomia); Peripheral neurofibromatosis (neurofibromatosis I);Peroneal muscular atrophy (Charcot-Marie-Tooth disease); peroxisomalalanine:glyoxylate aminotransferase deficiency (hyperoxaluria, primary);Peutz-Jeghers syndrome; Pfeiffer syndrome; Phenylalanine hydroxylasedeficiency disease (phenylketonuria); phenylketonuria; Pheochromocytoma(von Hippel-Lindau disease); Pierre Robin syndrome with fetalchondrodysplasia (Weissenbacher-Zweymoller syndrome); Pigmentarycirrhosis (hemochromatosis); PJS (Peutz-Jeghers syndrome); PKAN(pantothenate kinase-associated neurodegeneration); PKU(phenylketonuria); Plumboporphyria (ALA deficiency porphyria); PMA(Charcot-Marie-tooth disease); polyostotic fibrous dysplasia(McCune-Albright syndrome); polyposis cob (familial adenomatouspolyposis); polyposis, hamartomatous intestinal (Peutz-Jegherssyndrome); polyposis, intestinal, II (Peutz-Jeghers syndrome);polyps-and-spots syndrome (Peutz-Jeghers syndrome); Porphobilinogensynthase deficiency (ALA deficiency porphyria); porphyria; porphyrindisorder (porphyria); PPH (primary pulmonary hypertension); PPRdeficiency (variegate porphyria); Prader-Labhart-Willi syndrome(Prader-Willi syndrome); Prader-Willi syndrome; presenile and seniledementia (Alzheimer disease); primary hemochromatosis (hemochromatosis);primary hyperuricemia syndrome (Lesch-Nyhan syndrome); primary pulmonaryhypertension; primary senile degenerative dementia (Alzheimer disease);prion disease; procollagen type EDS VII, mutant (Ehlers-Danlos syndrome#arthrochalasia type); progeria (Hutchinson Gilford Progeria Syndrome);Progeria-like syndrome (Cockayne syndrome); progeroid nanism (Cockaynesyndrome); progressive chorea, chronic hereditary (Huntington)(Huntington's disease); progressive muscular atrophy (spinal muscularatrophy); progressively deforming osteogenesis imperfecta with normalsclerae (Osteogenesis imperfecte #type III); PROMM (Myotonic dystrophy#type 2); propionic academia; propionyl-CoA carboxylase deficiency(propionic acidemia); protein C deficiency; protein S deficiency;protoporphyria (erythropoietic protoporphyria); protoporphyrinogenoxidase deficiency (variegate porphyria); proximal myotonic dystrophy(Myotonic dystrophy #type 2); proximal myotonic myopathy (Myotonicdystrophy #type 2); pseudo-Gaucher disease; pseudo-Ullrich-Turnersyndrome (Noonan syndrome); pseudoxanthoma elasticum; psychosinelipidosis (Krabbe disease); pulmonary arterial hypertension (primarypulmonary hypertension); pulmonary hypertension (primary pulmonaryhypertension); PWS (Prader-Willi syndrome); PXE—pseudoxanthoma elasticum(pseudoxanthoma elasticum); Rb (retinoblastoma); Recklinghausen disease,nerve (neurofibromatosis 1); Recurrent polyserositis (Mediterraneanfever, familial); Retinal disorders; Retinitis pigmentosa-deafnesssyndrome (Usher syndrome); Retinoblastoma; Rett syndrome; RFALS type 3(Amyotrophic lateral sclerosis #type 2); Ricker syndrome (Myotonicdystrophy #type 2); Riley-Day syndrome (familial dysautonomia);Roussy-Levy syndrome (Charcot-Marie-Tooth disease); RSTS(Rubinstein-Taybi syndrome); RTS (Rett syndrome) (Rubinstein-Taybisyndrome); RTT (Rett syndrome); Rubinstein-Taybi syndrome; Sack-Barabassyndrome (Ehlers-Danlos syndrome, vascular type); SADDAN; sarcoma familysyndrome of Li and Fraumeni (Li-Fraumeni syndrome); sarcoma, breast,leukemia, and adrenal gland (SBLA) syndrome (Li-Fraumeni syndrome); SBLAsyndrome (Li-Fraumeni syndrome); SBMA (X-linked spinal-bulbar muscleatrophy); SCD (sickle cell anemia); Schwannoma, acoustic, bilateral(neurofibromatosis 2); SCIDX1 (X-linked severe combinedimmunodeficiency); sclerosis tuberose (tuberous sclerosis); SDAT(Alzheimer disease); SED congenita (spondyloepiphyseal dysplasiacongenita); SED Strudwick (spondyloepimetaphyseal dysplasia, Strudwicktype); SEDC (spondyloepiphyseal dysplasia congenita); SEMD, Strudwicktype (spondyloepimetaphyseal dysplasia, Strudwick type); senile dementia(Alzheimer disease #type 2); severe achondroplasia with developmentaldelay and acanthosis nigricans (SADDAN); Shprintzen syndrome (22q11.2deletion syndrome); sickle cell anemia; skeleton-skin-brain syndrome(SADDAN); Skin pigmentation disorders; SMA (spinal muscular atrophy);SMED, Strudwick type (spondyloepimetaphyseal dysplasia, Strudwick type);SMED, type I (spondyloepimetaphyseal dysplasia, Strudwick type); SmithLemli Dpitz Syndrome; South-African genetic porphyria (variegateporphyria); spastic paralysis, infantile onset ascending(infantile-onset ascending hereditary spastic paralysis); Speech andcommunication disorders; sphingolipidosis, Tay-Sachs (Tay-Sachsdisease); spinal-bulbar muscular atrophy; spinal muscular atrophy;spinal muscular atrophy, distal type V (Distal spinal muscular atrophy#type V); spinal muscular atrophy, distal, with upper limb predominance(Distal spinal muscular atrophy #type V); spinocerebellar ataxia;spondyloepimetaphyseal dysplasia, Strudwick type; spondyloepiphysealdysplasia congenital; spondyloepiphyseal dysplasia (collagenopathy,types II and XI); spondylometeepiphyseal dysplasia congenita, Strudwicktype (spondyloepimetaphyseal dysplasia, Strudwick type);spondylometaphyseal dysplasia (SMD) (spondyloepimetaphyseal dysplasia,Strudwick type); spondylometaphyseal dysplasia, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type); spongy degenerationof central nervous system (Canavan disease); spongy degeneration of thebrain (Canavan disease); spongy degeneration of white matter in infancy(Canavan disease); sporadic primary pulmonary hypertension (primarypulmonary hypertension); SSB syndrome (SADDAN); steely hair syndrome(Menkes syndrome); Steinert disease (myotonic dystrophy); Steinertmyotonic dystrophy syndrome (myotonic dystrophy); Stickler syndrome;stroke (CADASIL); Strudwick syndrome (spondyloepimetaphyseal dysplasia,Strudwick type); subacute neuronopethic Gaucher disease (Gaucher diseasetype 3); Swedish genetic porphyria (acute intermittent porphyria);Swedish porphyria (acute intermittent porphyria); Swiss cheese cartilagedysplasia (Kniest dysplasia); Tay-Sachs disease; TD—thanatophoricdwarfism (thanatophoric dysplasia); TD with straight femurs andcloverleaf skull (thanatophoric dysplasia #Type 2); Telangiectasia,cerebello-oculocutaneous (ataxia-telangiectasia); Testicularfeminization syndrome (androgen insensitivity syndrome);tetrahydrobiopterin deficiency; TFM—testicular feminization syndrome(androgen insensitivity syndrome); thalassemia intermedia (betathalassemia); Thalassemia Major (beta thalassemia); thanatophoricdysplasia; thiamine-responsive megaloblastic anemia with diabetesmellitus and sensorineural deafness; Thrombophilia due to deficiency ofcofactor for activated protein C, Leiden type (factor V Leidenthrombophilia); Thyroid disease; Tomaculous neuropathy (hereditaryneuropathy with liability to pressure palsies); Total HPRT deficiency(Lesch-Nyhan syndrome); Total hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome); Tourette's Syndrome;Transmissible dementias (prion disease); Transmissible spongiformencephalopathies (prion disease); Trencher Collins syndrome; Triasfragilitis ossium (osteogenesis imperfecta #Type I); triple X syndrome;Triplo X syndrome (triple X syndrome); Trisomy 21 (Down syndrome);Trisomy X (triple X syndrome); Troisier-Hanot-Chauffard syndrome(hemochromatosis); TS (Turner syndrome); TSD (Tay-Sachs disease); TSEs(prion disease); tuberose sclerosis (tuberous sclerosis); tuberoussclerosis; Turner syndrome; Turner syndrome in female with X chromosome(Noonan syndrome); Turner's phenotype, karyotype normal (Noonansyndrome); Turner's syndrome (Turner syndrome); Turner-like syndrome(Noonan syndrome); Type 2 Gaucher disease (Gaucher disease type 2); Type3 Gaucher disease (Gaucher disease type 3); UDP-galactose-4-epimerasedeficiency disease (galactosemia); UDP glucose 4-epimerase deficiencydisease (galactosemia); UDP glucose hexose-1-phosphateuridylyltransferase deficiency (galactosemia); Ullrich-Noonan syndrome(Noonan syndrome); Ullrich-Turner syndrome (Turner syndrome);Undifferentiated deafness (nonsyndromic deafness); UPS deficiency (acuteintermittent porphyria); Urinary bladder cancer (bladder cancer); URODdeficiency (porphyria cutanea tarda); Uroporphyrinogen decarboxylasedeficiency (porphyria cutanea tarda); Uroporphyrinogen synthasedeficiency (acute intermittent porphyria); UROS deficiency (congenitalerythropoietic porphyria); Usher syndrome; UTP hexose-1-phosphateuridylyltransferase deficiency (galactosemia); Van Bogaert-Bertrandsyndrome (Canavan disease); Van der Hoeve syndrome (osteogenesisimperfecta #Type I); variegate porphyria; Velocardiofacial syndrome(22q11.2 deletion syndrome); VHL syndrome (von Hippel-Lindau disease);Vision impairment and blindness (Alstrom syndrome); Von Bogaert-Bertranddisease (Canavan disease); von Hippel-Lindau disease; VonRecklenhausen-Applebaum disease (hemochromatosis); von Recklinghausendisease (neurofibromatosis 1); VP (variegate porphyria); Vrolik disease(osteogenesis imperfecta); Waardenburg syndrome; Warburg Sjo FledeliusSyndrome (Micro syndrome); WD (Wilson disease); Weissenbacher-Zweymollersyndrome; Wilson disease; Wilson's disease (Wilson disease);Wolf-Hirschhorn syndrome; Wolff Periodic disease (Mediterranean fever,familial); WZS (Weissenbacher-Zweymoller syndrome); XerodermaPigmentosum; X-linked mental retardation and macroorchidism (fragile Xsyndrome); X-linked primary hyperuricemia (Lesch-Nyhan syndrome);X-linked severe combined immunodeficiency; X-linked sideroblasticanemia; X-linked spinal-bulbar muscle atrophy (Kennedy disease);X-linked uric aciduria enzyme defect (Lesch-Nyhan syndrome); X-SCID(X-linked severe combined immunodeficiency); XLSA (X-linkedsideroblastic anemia); XSCID (X-linked severe combinedimmunodeficiency); XXX syndrome (triple X syndrome); XXXX syndrome (48,XXXX); XXXXX syndrome (49, XXXXX); XXY syndrome (Klinefelter syndrome);XXY trisomy (Klinefelter syndrome); XYY karyotype (47,XYY syndrome); XYYsyndrome (47,XYY syndrome); and YY syndrome (47,XYY syndrome).

Moreover, a disease in the context of the present invention maypreferably be any disease, disorder or condition indicated in feature c5of Tablet preferably for the therapeutic protein encoded by the at leastone coding sequence of the RNA according to the invention.

In a further preferred aspect, the RNA according to the invention or the(pharmaceutical) composition comprising the RNA according to theinvention (or a plurality of inventive RNAs as defined herein) may beused for the preparation of a pharmaceutical composition, particularlyfor purposes as defined herein, preferably for the use in gene therapyin the treatment or prevention of diseases as defined herein.

The (pharmaceutical) composition may furthermore be used in gene therapyparticularly in the treatment of a disease or a disorder, preferably asdefined herein.

According to a further aspect, the present invention also provides kits,particularly kits of parts. Such kits, particularly kits of parts,typically comprise as components alone or in combination with furthercomponents as defined herein at least one inventive RNA species asdefined herein, or the inventive (pharmaceutical) composition comprisingthe RNA according to the invention. The at least one RNA as definedherein, is optionally in combination with further components as definedherein, whereby the at least one RNA is provided separately (first partof the kit) from at least one other part of the kit comprising one ormore other components. The (pharmaceutical) composition may occur in oneor different parts of the kit. As an example, e.g. at least one part ofthe kit may comprise at least one RNA as defined herein, and at leastone further part of the kit at least one other component as definedherein, e.g. at least one other part of the kit may comprise at leastone (pharmaceutical) composition or a part thereof, e.g. at least onepart of the kit may comprise the RNA as defined herein, at least onefurther part of the kit at least one other component as defined herein,at least one further part of the kit at least one component of the(pharmaceutical) composition or the (pharmaceutical) composition as awhole, and at least one further part of the kit e.g. at least onepharmaceutical carrier or vehicle, etc. In case the kit or kit of partscomprises a plurality of RNAs as described herein, one component of thekit can comprise only one, several or all RNAs comprised in the kit. Inan alternative embodiment every/each RNA species may be comprised in adifferent/separate component of the kit such that each component forms apart of the kit. Also, more than one RNA as defined herein may becomprised in a first component as part of the kit, whereas one or moreother (second, third etc.) components (providing one or more other partsof the kit) may either contain one or more than one RNA as definedherein, which may be identical or partially identical or different fromthe first component. The kit or kit of parts may furthermore containtechnical instructions with information on the administration and dosageof the RNA according to the invention, the (pharmaceutical) compositionof the invention or of any of its components or parts, e.g. if the kitis prepared as a kit of parts.

Also comprised by the present invention are methods of treating orpreventing a disease or disorder, preferably as defined herein, byadministering to a subject in need thereof a pharmaceutically effectiveamount of the RNA or the pharmaceutical composition according to theinvention. Such a method typically comprises an optional first step ofpreparing the RNA or the composition of the present invention, and asecond step, comprising administering (a pharmaceutically effectiveamount of) said composition to a patient/subject in need thereof. Asubject in need thereof will typically be a mammal. In the context ofthe present invention, the mammal is preferably selected from the groupcomprising, without being limited thereto, e.g. goat, cattle, swine,dog, cat, donkey, monkey, ape, a rodent such as a mouse, hamster, rabbitand, particularly, human, wherein the mammal typically suffers from adisease or disorder as defined herein.

As described above, it is referenced throughout the application to Table1.

Each protein entry in that table, i.e. beginning with the number sign #and ending with a semicolon (;) corresponds to a preferred therapeuticprotein as defined herein and provides the abbreviation of the name ofthe peptide or protein indicated under feature c1 (“Peptide or protein”)and the NCBI database accession number of that peptide or protein inthat entry under feature c2 (“NCBI Ref Seq ID”). Feature c3 of thatentry provides the SEQ ID NO: (as comprised in the sequence listingherein) corresponding to the amino acid sequence of that peptide orprotein. Feature c4 of that entry provides the SEQ ID NO: (as comprisedin the sequence listing herein) corresponding to the nucleic acidsequence of preferred RNA's encoding that peptide or protein. Feature c5provides one or more disease, disorder or condition, for the treatmentor prevention of which the peptide or protein identified by features c1to c4 of that entry is preferably used. Table 1 starts with entry“c1(37135 (Sep-01)) c2(NP_443040) c3(1) c4(26115, 39172, 52229, 13058,65286) c5(d, c, e, b)” and ends with entry “c1(ZZZ3) c2(XP_011539507)c3(13057) c4(39171, 52228, 65285, 26114, 78342) c5(aA)” (all inaccordance with the formula and the Abbreviation Dictionary as describedabove; number signs (#) and semicolons were introduced for ease ofreadability to separate the different entries from another).

Lengthy table referenced here US20220025369A1-20220127-T00001 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20220025369A1-20220127-T00002 Pleaserefer to the end of the specification for access instructions.

DESCRIPTION OF THE FIGURES

FIG. 1: FIG. 1a shows that engineered, unmodified mouse Epo mRNA yieldedhigher protein levels in mice than the corresponding pseudouridinemodified sequence. 1 μg of either unmodified or pseudouridine modifiedmRNA encoding erythropoietin was complexed with TransIT andintraperitoneally injected into mice. Serum erythropoietin (EPO) levelswere determined at different times (1, 2, or 3 days) afteradministration.

FIG. 1b shows that low nanogram doses of engineered, unmodified mouseEpo mRNA gave rise to substantial protein levels in murine serum. Theindicated amounts of TransIT-complexed unmodified Epo mRNA wereadministered intraperitoneally. As a control, 100 U of recombinant humanEPO protein (hEPO) were given intraperitoneally. Serum EPO levels weredetermined 24 hours after treatment. Unmodified, engineered mRNAharboring the nucleotides A, U, G, and C; ψ, engineered mRNA in whichpseudouridine replaces U. n=4 for all groups.

FIG. 2: FIG. 2a shows that sequence engineered Epo mRNA elicited strongreticulocyte responses in mice after intraperitoneal injection witheither TransIT-complexed mRNA (1 μg) or recombinant erythropoietin (EPO)protein (hEPO: 100 U, MmEpo: 800 ng). mRNA was either unmodified orharbored pseudouridine. The level of reticulocytes was determined 4 daysafter treatment.

FIG. 2b shows that low nanogram doses of engineered but unmodified mouseEpo mRNA elicited substantial reticulocyte responses in mice uponintraperitoneal administration of the indicated doses ofTransIT-complexed Epo mRNA or 100 U of hEPO. Reticulocytes werequantified 4 days after injection.

FIG. 2c shows that sequence-engineered mouse Epo mRNA substantiallyincreased the hematocrit in mice upon treatment with eitherTransIT-complexed mRNA (1 μg) or recombinant EPO protein (hEPO: 100 U,MmEpo: 800 ng) on day 0 and 14. The hematocrit was measured on day 18.

mRNA was either unmodified or harbored pseudouridine. unmodifiedengineered mRNA harboring the nucleotides A, U, G, and C; ψ, engineeredmRNA in which pseudouridine replaces U; hEPO, recombinant human Epoprotein; MmEpo, recombinant murine Epo protein. n=4 for all groups.

FIG. 3: FIG. 3a shows that engineered, unmodified Epo mRNA allowedlong-term/continued treatment of mice as protein yield fromintraperitoneally administered mouse Epo mRNA was not affected byrepeated treatments. Mice were repeatedly injected with 1 μg of eitherunmodified or pseudouridine-modified mRNA as well as 0.1 μg ofunmodified mRNA at an interval of 2 weeks. Plasma erythropoietin (EPO)levels were determined 24 hours after each treatment.

FIG. 3b shows that intraperitoneally injected mouse Epo mRNA increasedreticulocyte counts even after multiple dosing. Mice received multipledoses of TransIT-complexed mRNA (1 μg, either unmodified orpseudouridine-modified) or MmEpo (0.8 μg) at a biweekly intervalstarting on day 0 and were analyzed for reticulocytes 4 days aftertreatments.

FIG. 3c shows that repeated intraperitoneal injections of Epo mRNAelicited a strong and sustained increase of the hematocrit. Micereceived multiple doses of TransIT-complexed mRNA (1 μg, eitherunmodified or pseudouridine-modified) or MmEpo (0.8 μg) at a biweeklyinterval starting on day 0 and were analyzed for the hematocrit atvarious times. n=4 for all groups.

FIG. 4: FIG. 4a (figure's left column) shows that intravenous mRNAinjection into pigs gave rise to high serum erythropoietin (EPO) levelsas well as to substantial physiological effects. Animals received 1.3 mgof lipid nanoparticle (LNP) encapsulated porcine Epo mRNA (0.065 mg/kg)on day 0 and were analyzed for EPO levels and hematological parametersat various times. Protein levels before treatment were below the limitof detection of the assay. Distinct symbols were assigned to individualanimals.

FIG. 4b (figure's right column) shows that intravenous mRNA injectioninto macaques increased EPO levels, reticulocyte numbers as well as thehematocrit. Animals received 100 μg of LNP encapsulated M. fascicularisEpo mRNA (0.037 mg/kg) and were analyzed for EPO levels andhematological parameters before and at various times after treatment.Distinct symbols were assigned to individual animals.

“Pre” corresponds to prevalue before treatment, n=3 for pig experiment,n=4 for macaque study.

EXAMPLES

In the following, particular examples illustrating various embodimentsand aspects of the invention are presented. However, the presentinvention shall not to be limited in scope by the specific embodimentsdescribed herein. The following preparations and examples are given toenable those skilled in the art to more clearly understand and topractice the present invention. The present invention, however, is notlimited in scope by the exemplified embodiments, which are intended asillustrations of single aspects of the invention only, and methods whichare functionally equivalent are within the scope of the invention.Indeed, various modifications of the invention in addition to thosedescribed herein will become readily apparent to those skilled in theart from the foregoing description, accompanying figures and theexamples below. All such modifications fall within the scope of theappended claims.

Example 1 Preparation of DNA and mRNA Constructs

For the present examples, DNA sequences encoding Mus musculuserythropoietin (MmEpo), pig erythropoietin (Sus scrofa; SsEpo), andmacaque erythropoietin (Macaca fascicularis; MfEpo) were prepared andused for subsequent RNA in vitro transcription reactions. The obtainedmRNA constructs were used for further in vitro and in vivo experiments.The respective amino acid sequences, the mRNA sequences of MmEpo, SsEpo,and MfEpo as well as preparation details are provided below.

For mRNA sequence engineering, the codons of the open reading frame wereadapted according to a proprietary optimization protocol as described inEP 1392341 and EP 1800697 in order to improve translation and half-lifeof the mRNA. To provide the optimized ORF sequence with an optimalcombination of untranslated sequences, it was subjected to a screeningprocess applying preselected sequences. For this preselection ofefficacious regulatory sequences, various biological sources werescreened for potent enhancer and stabilizer elements (furtherinformation is described in patent publications WO 2013/143598 and WO2013/143599).

For mouse (Mus musculus; MmEpo), pig (Sus scrofa; SsEpo), and macaque(Macaca fascicularis; MfEpo) erythropoietin, only the corresponding RNAsequences of the DRF cassettes (excluding the flanking cloning sitesAAGCTT and ACTAGT indicated by three dots in each 5′ and 3′ end of therespective sequence) are shown.

MmEpo (SEQ ID NO: 78365)  . . . AUGGGCGUGCCCGAGCGGCCGACCCUGCUCCUGCUGCUCAGCCUGCUGCUCAUCCCCCUGGGG CUGCCCGUCCUCUGCGCCCCCCCGCGCCUGAUCUGCGACUCCCGGGUGCUGGAGCGCUACAUCCUCGAGG CCAAGGAGGCGGAGAACGUGACCAUGGGCUGCGCCGAGGGGCCCCGGCUGAGCGAGAACAUCACGGUCCC CGACACCAAGGUGAACUUCUACGCCUGGAAGCGCAUGGAGGUGGAGGAGCAGGCCAUCGAGGUCUGGCAG GGCCUGUCCCUCCUGAGCGAGGCCAUCCUGCAGGCGCAGGCCCUCCUGGCCAACUCCAGCCAGCCCCCGG AGACACUGCAGCUCCACAUCGACAAGGCCAUCUCCGGGCUGCGGAGCCUGACCUCCCUCCUGCGCGUGCU GGGCGCGCAGAAGGAGCUCAUGAGCCCGCCCGACACGACCCCCCCGGCCCCGCUGCGGACCCUGACCGUG GACACGUUCUGCAAGCUCUUCCGCGyCUACGCCAACUUCCUGCGGGGCAAGCUGAAGCUCUACACCGGGG AGGUGUGCCGCCGGGGCGACCGCUGA . . .SsEpo (SEQ ID NO: 78367)  . . . AUGGGCGCCCGCGAGUGCCCCGCCCGGCUGCUCCUGCUGAGCCUCCUGCUGCUCCCGCUGGGG CUGCCCGUGCUCGGCGCGCCCCCGCGCCUGAUCUGCGACUCCCGGGUCCUGGAGCGCUACAUCCUCGAGG CCAAGGAGGGGGAGAACGCCACCAUGGGCUGCGCCGAGAGCUGCUCCUUCAGCGAGAACAUCACCGUGCC GGACACGAAGGUGAACUUCUACGCCUGGAAGCGGAUGGAGGUCCAGCAGCAGGCGAUGGAGGUGUGGCAG GGGCUGGCCCUGCUCUCCGAGGCCAUCCUGCAGGGCCAGGCCCUGCUCGCGAACAGCUCCCAGCCCAGCG AGGCCCUGCAGCUGCACGUGGACAAGGCCGUCUCCGGCCUCCGCAGCCUGACCUCCCUGCUCCGGGCCCU GGGGGCCCAGAAGGAGGCGAUCCCCCUGCCCGACGCCAGCCCGUCCAGCGCCACCCCGCUCCGCACCUUC GCCGUGGACACGCUGUGCAAGCUGUUCCGGAACUACUCCAACUUCCUCCGCGGCAAGCUGACCCUGUACA CCGGGGAGGCCUGCCGGCGCCGGGACCGCUGA . . . MfEpo (SEQ ID NO: 78369)  . . . AUGGGCGUGCACGAGUGCGCGGCCUGGCUCUGGCUGCUGCUCAGCCUGOUGAGCCUGCCCCUG GGGCUGCCCGUCCCCGGCGCCCCGCCGCGGCUGAUCUGCGACUCCCGCGUGCUGGAGCGGUACCUCCUCG AGGCCAAGGAGGCGGAGAACGUGACCAUGGGCUGCUCCGAGAGCUGCUCCCUGAACGAGAACAUCACGG UCCCCGACACCAAGGUGAACUUCUACGCCUGGAAGCGGAUGGAGGUGGGGCAGCAGGCCGUCGAGGUCUG GCAGGGCCUGGCCCUCCUGAGCGAGGCCGUGCUGCGCGGCCAGGCCGUGCUGGCCAACUCCAGCCAGCCC UUCGAGCCGCUGCAGCUCCACAUGGACAAGGCCAUCUCCGGGCUGCGCAGCAUCACCACCCUCCUGCGGG CGCUGGGCGCGCAGGAGGCCAUCAGCCUGCCCGACGCCGCCAGCGCCGCCCCGCUGCGCACCAUCACCGC GGACACGUUCUGCAAGCUCUUCCGGGUCUACUCCAACUUCCUGCGCGGCAAGCUGAAGCUCUACACCGG GGAGGCCUGCCGGCGCGGCGACCGGUGA . . .

The corresponding full-length constructs are shown in SEQ ID NO: 78366(MmEpo, R3134), SEQ ID NO: 78368 (SsEpo, R3460) and SEQ ID NO: 78370(MfEpo, R3516). The constructs were prepared by introducing a 5′-TOP-UTRderived from the ribosomal protein 32L or HSD17B4, modifying the wildtype coding sequence by introducing a GC-optimized sequence forstabilization, followed by a stabilizing sequence derived from thealbumin-3′-UTR, a stretch of 64 adenosines (poly(A)-sequence), a stretchof cytosines (poly(C)-sequence), and a histone stem loop.

mRNA was produced according to CureVac's PUREmessenger® technology. Inbrief, enzymatically linearized plasmid harboring the sequence ofinterest downstream of a T7 promoter was transcribed in vitro using T7RNA polymerase (Thermo Scientific). MfEpo (R3516) RNA was enzymaticallycapped. MmEpo (R3134) and SsEpo (R3460) were co-transcriptionallycapped. For this, m7G capping using cap analog (m7GpppG) and2′-0-methyltransferase kits (CellScript Script Cap m7G Capping System)were used. Further, an additional poly(A) sequence was generated byenzymatic polyadenylation using a commercially available polyadenylationkits and corresponding protocols known in the art (CellScript A-PlusPoly(A) Polymerase Tailing Kit).

For experiments with chemically-modified nucleosides, 100% replacementwas used for mRNAs harboring chemically-modified nucleosides. All mRNAslacking modified nucleosides (sequence-engineered or not) as well as allnucleoside-modified mRNAs were purified according to the same protocolby reversed-phase chromatography using a PLRP-S stationary phase and anacetonitrile gradient in a triethylammonium acetate buffer (Karike etal., 2011, Nucleic Acids Res 39: el42).

Example 2 Formulation of mRNA Constructs

For intraperitoneal administration, mRNAs were formulated withTransIT-mRNA (Mirus Bio, Madison, USA) according to Karike et al. (2012,Mol Ther 20: 948-953). Intravenous administration of mRNA to macaques orpigs was conducted using mRNA encapsulated in LNPs by AcuitasTherapeutics (Vancouver, Canada; LNP formulation according to Jayaramanet al., 2012, Angew Chem Int Ed Engl 51: 8529-8533; Maier et al., 2013,Mol Ther 21:1570-1578; and Coelho et al. 2013, N Engl J Med369:819-829). LNPs were prepared using a self-assembly process in whichan aqueous solution of mRNA at pH 4.0 is rapidly mixed with a solutionof lipids dissolved in ethanol. LNPs contained an ionizable cationiclipid/phosphatidylcholine/cholesterol/PEG-lipid (50:10:38.5:1.5mol/mol), encapsulated RNA-to-total lipid ratio of ˜0.05 (wt/wt) and adiameter of ˜80 nm. At blood pH, LNPs exhibited a net neutral surfacecharge but become positively charged in acidified endosomes followingApoE-mediated endocytosis by hepatocytes in vivo, which resulted inendosome disruption and release of mRNA into the cytoplasm.

Example 3 Analysis of In Vivo Erythropoietin Protein Levels andPhysiological Parameters Reticulocytes, Hematocrit and EPO-specificAntibody Responses

EPO Level Measurements

For quantification of EPO levels in mice, a mouse EPO ELISA kit (REDSystems, Wiesbaden, Germany) was also used to determine EPO levels inthe plasma of treated mice. For plasma preparation, a few microliters ofblood were collected, heparinized, and centrifuged.

For quantification of EPO levels in pigs, blood samples were collectedinto serum vials, kept at room temperature for at least 20 minutes, andcentrifuged. Porcine EPO levels in the supernatant were measured using amouse EPO ELISA kit (R&D Systems) with cross reactivity to pig EPO andrecombinant pig EPO protein (Cusabio, Wuhan, China) as standard.

For quantification of EPO levels in serum of cynomolgus monkeys a humanEPO ELISA kit was used (R&D Systems) that cross reacts with macaque EPO.

Detection of EPO-specific Antibody Responses

Induction of EPO-specific antibodies in response to repeated treatmentswith Epo mRNA was analyzed by enzyme-linked immunosorbent assay (ELISA).Therefore, plates were coated with mouse EPO protein and incubated withplasma from mice 4 weeks after they received six injections of mRNA orcontrol solution within 3 weeks. As positive control, a rat anti-mouseEPO antibody (R&D Systems) was applied in the ELISA. EPO-specificantibodies were detected with goat anti-mouse and anti-rat IgG antiseralabelled with peroxidase. The ELISA allowed detection of a concentrationof anti-EPO antibody as low as about 100 μg/ml.

Physiological parameters, such as the number of reticulocytes and thehematocrit, were measured as follows:

Reticulocyte Count Measurements

For determination of reticulocyte counts in mice, a small volume ofblood was drawn from animals, mixed with an appropriate amount ofheparin, and analyzed using Retic-COUNT (BD Biosciences, Heidelberg,Germany) according to the manufacturer's instructions. Stained cellswere analyzed on a FACS Canto (BD Biosciences). Reticulocyte levels aregiven as percentage of total red blood cells.

For determination of reticulocyte counts in pigs, blood was drawn fromthe cranial vein and collected into ethylenediaminetetraacetate(EDTA)-coated vials. Reticulocytes were measured using a SysmexXT-2000iV automated hematology analyzer at Aurigon. Reticulocyte levelsare given as percentage of total red blood cells.

For determination of reticulocyte counts in cynomolgus monkeys, bloodwas collected from a suitable vein, EDTA was added as anticoagulant, andreticulocytes were counted with an Advia 120 hematology system atHuntingdon.

Hematocrit Determinations

For mice, the volume ratio of blood cells was determined usinghematocrit capillaries (KABE Labortechnik, Nombrecht-Elsenroth,Germany). In brief, capillaries were filled with heparinized blood,sealed on one end with wax (Hirschmann Laborgerate, Eberstadt, Germany),centrifuged, and analyzed according to the manufacturer's instructions.

For pigs and macaques, hematocrits were determined with a SysmexXT-2000iV and Advia 120 hematology analyzer, respectively.

Example 4 Administration of mRNA Coding for Epo to Mice, Pigs and NHP

Erythropoietin encoding mRNA as described above was administered tomice, pigs and NHP (cynomolgus monkeys).

BALB/c female mice 7-9 weeks of age were purchased from Janvier Labs (LeGenest-Saint-Isle, France). For intraperitoneal injections,TransIT-formulated mRNA encoding murine EPO as described above wasadministered in a total volume of 100 μl (either 5 ng, 50 ng, or 500 ngor respectively 0.065 mg/kg, depending on the experiment).

Hungarian large white, domestic pigs (female, approximately 20 kg) werehoused and experiments were conducted at ATRC Aurigon Toxi-Coop ResearchCenter (Dunakeszi, Hungary). For intraperitoneal injection, 360 μg ofTransIT-formulated mRNA encoding porcine EPO as described above wasadministered in a total volume of 25 ml. Animals received two injectionson consecutive days. For intravenous administration, pigs received 1.3mg (0.065 mg/kg) of porcine Epo mRNA formulated with LNPs inphosphate-buffered saline pH 7.4. The total volume per animal was 26 ml.

Cynomolgus monkeys (2.5-2.8 kg) were housed and experiments wereperformed at Huntingdon Life Science (Huntingdon, UK). Animals receiveda single intravenous injection of a weight-adjusted dose (0.037 mg/kg)similar to that in mice, corresponding to a dose of LNP-formulated mRNA(100 μg) encoding EPO from Macaca fascicularis as described above inphosphate buffered saline pH 7.4. The total volume for intravenousinjections was 2 ml.

Example 5 Mice In Vivo Epo Levels Upon Administration of mRNA Coding forEpo

TransIT-complexed sequence-engineered mEpo mRNA was administeredintraperitoneal to mice as described above. As apparent from FIG. 1a ,sequence-engineered but unmodified mRNA in mice yielded in high proteinexpression and also was superior to nucleoside-modified variants. Asapparent, 1 μg of either unmodified or pseudouridine modified mRNAencoding erythropoietin was complexed with TransIT and intraperitoneallyinjected into mice. Serum erythropoietin (EPO) levels were determined atdifferent times (1, 2, or 3 days) after administration.

Further, as apparent from FIG. 1b low nanogram doses of engineered,unmodified mouse Epo mRNA gave rise to substantial protein levels inmurine serum (amounts of TransIT-complexed unmodified Epo mRNA whichwere administered intraperitoneally are indicated). As a control, 100 Uof recombinant human EPO protein (hEPO) were given intraperitoneally.

Administration of MmEpo-encoding mRNA caused a burst release ofreticulocytes representing precursors of mature erythrocytes into theblood stream as apparent from increased reticulocyte numbers in mice(FIG. 2a ). As apparent, sequence-engineered mRNA outperformed itspseudouridine-modified counterpart (P<0.01, Student's t-test); all dosesdown to 10 ng of unmodified mRNA significantly increased reticulocytenumbers (FIG. 2b ) (P<0.05 for 10 ng versus untreated, Student'st-test). Likewise, sequence-engineered mouse Epo mRNA substantiallyincreased the hematocrit in mice (FIG. 2c ).

Also, as apparent from Example 9 “Measurement of cytokine secretion inmice and NHP” further below, chemically unmodified mRNA did notstimulate a suppressive (immune) response.

Example 6 EPO Expression and Corresponding Physiological Responses UponRepeated Treatments in Mice

For evaluating physiological responses upon repeated treatments in mice,mice received a highly effective dose of TransIT-complexedsequence-engineered mRNA, either unmodified or pseudouridine-modified,every other week. As apparent from FIG. 3a , during the treatmentperiod, doses did not lose efficacy with respect to serum EPO levelsobtained 24 hours after administration (P=0.235 for 1 μg mRNA, analysisof variance).

As apparent from FIG. 3b , sequence-engineered mRNA elicited higherprotein levels than its nucleoside-modified counterpart. In contrast toconstant EPO responses, reticulocyte responses to sequential injectionsdeclined to some extent over time.

As opposed to mice receiving murine recombinant EPO protein,mRNA-injected animals were characterized by strongly elevatedhematocrits (P<0.01 for 1 μg versus untreated on all days, Student'st-test) as well as erythropoiesis induced splenomegaly in the absence ofany other disturbances of the spleen (FIG. 3c ).

Example 7 Pigs In Vivo Epo Levels Upon Administration of mRNA Coding forEpo

As described above, pigs were treated with a single intravenous dose ofsequence-engineered, unmodified mRNA (0.065 mg/kg) encapsulated in LNPs.The resulting high serum EPO levels are shown in FIG. 4a . As aconsequence, reticulocyte numbers were strongly increased and animalsshowed a substantial and sustained elevation of the hematocrit (P<0.05for day 12 versus pretreatment, Student's t-test) (see FIG. 4a ).

Example 8 NHP In Vivo Epo Levels Upon Administration of mRNA Coding forEpo

NHP showed very high serum EPO levels and strong physiological responsesin vivo after single intravenous dose of sequence-engineered, unmodifiedmRNA encapsulated in LNPs (FIG. 4b ). As a consequence, reticulocytenumbers were strongly increased and animals showed a substantial andmeaningful raise of the hematocrit (increase for each individual frompretreatment to 96 hours after treatment; P<0.05 for 96 hours versuspretreatment, Student's t-test). (FIG. 4b ).

As apparent from Example 9 “Measurement of cytokine secretion in miceand NHP” further below, chemically unmodified mRNA did not stimulate asuppressive (immune) response.

Example 9 Measurement of Cytokine Secretion in Mice and NHP

Mice received 6 injections of TransIT-complexed mRNA or controlsolutions within 3 weeks. 6 hours after the first and last treatment,blood was collected, heparinized, and plasma preparations were analyzedfor various cytokines. TNFA, 1L-6 and IFNG were measured by CytometricBead Array (CBA) analysis (BD Biosciences, Heidelberg, Germany).

Macaques received a single injection of LNP-encapsulated M. fascicularisEpo mRNA. Before and 6 hours after treatment, blood was drawn andsamples were analyzed for cytokines using the MILLIPLEX Map Non-humanprimate cytokine magnetic bead panel kit (Merck Millipore, Schwalbach,Germany) at Huntingdon.

Results: immunostimulation of mRNA was at background levels.

None of the mice showed any substantial cytokine release upon mRNAadministration; all measurements lay within the range observed for theformulation reagent only (data not shown). Similar results were obtainedafter six administrations within 3 weeks (data not shown).

Further, similar to mice, there was no detectable cytokine release upontreatment in NHP upon single intravenous injection of a weight-adjusteddose (0.037 mg/kg) similar to that in mice as described above. (data notshown).

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20220025369A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A purified RNA comprising at least one coding sequence, wherein thecoding sequence comprises a nucleic acid sequence selected from thegroup consisting of nucleic acid sequences according to any one of SEQID NO: 13058 to 78342 or a sequence at least 80% identical to any one ofSEQ ID NO: 13058 to
 78342. 2. The RNA according to claim 1, wherein theat least one coding sequence encodes a peptide or protein comprising atherapeutic protein, wherein the therapeutic protein is selected from(i) therapeutic proteins for use in the treatment of metabolic orendocrine disorders, (ii) therapeutic proteins for use in the treatmentof blood disorders, diseases of the circulatory system, diseases of therespiratory system, cancer or tumour diseases, infectious diseases orimmunedeficiencies, (iii) therapeutic proteins used for hormonereplacement therapy, (iv) therapeutic proteins used for reprogramming ofsomatic cells into pluri- or omnipotent stem cells, and (v) therapeuticproteins selected from adjuvant or immunostimulating proteins.
 3. TheRNA according to claim 1, wherein the encoded peptide or proteincomprises a therapeutic protein or a fragment or variant thereof,selected from the group consisting of 37135 (Sep-01); 37500 (Sep-02);37865 (Sep-03); 38231 (Sep-04); 38596 (Sep-05); 38961 (Sep-06); 39326(Sep-07); 40057 (Sep-09); 40422 (Sep-10); 40787 (Sep-11); 41153(Sep-12); 41883 (Sep-14); A1BG; A1CF; A2M; A2ML1; A4GNT; AAAS; AACS;AADAC; AAGAB; AAK1; AANAT; AARD; AARS2; AARS; AASDH; AASDHPPT; AASS;AATF; AATK; ABAT; ABCA12; ABCA13; ABCA1; ABCA2; ABCA3; ABCA5; ABCA6;ABCA7; ABCA9; ABCB11; ABCB1; ABCB4; ABCB5; ABCB6; ABCB7; ABCB8; ABCB9;ABCC10; ABCC11; ABCC12; ABCC1; ABCC2; ABCC3; ABCC4; ABCC5; ABCC6; ABCC8;ABCC9; ABCD1; ABCD2; ABCD3; ABCD4; ABCE1; ABCF1; ABCF2; ABCG1; ABCG2;ABCG4; ABCG5; ABCG8; ABHD12B; ABHD12; ABHD16A; ABHD17B; ABHD2; ABHD5;ABHD6; ABI1; ABI2; ABI3BP; ABI3; ABL1; ABL2; ABLIM1; ABLIM2; ABO; ABRA;ABR; ABT1; ACAA1; ACAA2; ACACA; ACACB; ACAD10; ACAD8; ACAD9; ACADL;ACADSB; ACADS; ACADVL; ACAN; ACAT1; ACAT2; ACBD3; ACBD4; ACBD5; ACBD6;ACCS; ACD; ACE2; ACE; ACER2; ACER3; ACHE; ACIN1; ACKR1; ACKR2; ACKR3;ACKR4; ACLY; ACMSD; ACO1; ACO2; ACOT13; ACOT1; ACOT2; ACOT9; ACOX1;ACOX2; ACOX3; ACOXL; ACP1; ACP2; ACP5; ACP6; ACPP; ACRBP; ACRC; ACR;ACRV1; ACSBG1; ACSBG2; ACSF3; ACSL1; ACSL3; ACSL5; ACSL6; ACSM1; ACSM2B;ACSM3; ACSS1; ACSS2; ACSS3; ACTA1; ACTA2; ACTB; ACTBL2; ACTC1; ACTG1;ACTG2; ACTL6A; ACTL6B; ACTL8; ACTL9; ACTN1; ACTN2; ACTN3; ACTN4; ACTR1A;ACTR1B; ACTR2; ACTR3B; ACTR3; ACTR5; ACTRT1; ACVR1B; ACVR1C; ACVR1;ACVR2A; ACVR2B; ACVRL1; ACY1; ACY3; ACYP2; ADAD1; ADA; ADAM10; ADAM11;ADAM12; ADAM15; ADAM17; ADAM19; ADAM20; ADAM21; ADAM22; ADAM23; ADAM28;ADAM29; ADAM2; ADAM33; ADAM7; ADAM8; ADAM9; ADAMDEC1; ADAMTS10;ADAMTS12; ADAMTS13; ADAMTS14; ADAMTS15; ADAMTS16; ADAMTS17; ADAMTS18;ADAMTS19; ADAMTS1; ADAMTS20; ADAMTS2; ADAMTS3; ADAMTS4; ADAMTS5;ADAMTS6; ADAMTS7; ADAMTS8; ADAMTS9; ADAMTSL1; ADAMTSL2; ADAMTSL3;ADAMTSL4; ADAMTSL5; ADAP1; ADAP2; ADARB1; ADARB2; ADAR; ADAT2; ADAT3;ADCK3; ADCK4; ADCY10; ADCY1; ADCY2; ADCY3; ADCY5; ADCY6; ADCY7; ADCY8;ADCY9; ADCYAP1; ADCYAP1R1; ADD1; ADD2; ADD3; ADGB; ADGRA1; ADGRA2;ADGRA3; ADGRB1; ADGRB2; ADGRB3; ADGRD1; ADGRD2; ADGRE1; ADGRE2; ADGRE5;ADGRF5; ADGRG1; ADGRG2; ADGRG3; ADGRG6; ADGRG7; ADGRL1 ; ADGRL3; ADGRV1;ADH1A; ADH1B; ADH4; ADH5; ADH6; ADH7; ADHFE1; ADI1; ADIG; ADIPOQ;ADIPOR1; ADIPOR2; ADIRF; ADK; ADM2; ADM; ADNP; ADO; ADORA1; ADORA2A;ADORA2B; ADPGK; ADPRH; ADPRHL1; ADPRHL2; ADRA1A; ADRA1B; ADRA1D; ADRA2A;ADRA2B; ADRA2C; ADRB1; ADRB2; ADRB3; ADRBK1; ADRBK2; ADRM1; ADSL; ADSS;ADSSL1; AUTRP; AEBP2; AEN; AES; AFAP1; AFAP1L1; AFAP1L2; AFF1; AFF2;AFF3; AFF4; AFG3L2; AFM; AFP; AGA; AGAP1; AGAP2; AGAP3; AGAP4; AGBL1;AGBL2; AGBL3; AGBL4; AGER; AGFG1; AGFG2; AGGF1; AGK; AGMO; AGO2; AGPAT1;AGPAT2; AGPAT3; AGPAT4; AGPAT9; AGPS; AGR2; AGR3; AGRN; AGRP; AGT;AGTPBP1; AGTR1; AGTR2; AGXT2; AGXT; AHCY; AHCYL2; AHI1; AHNAK; AHR;AHRR; AHSA1; AHSA2; AHSG; AICDA; AIDA; AIF1; AIFM1; AIFM2; AIFM3; AIG1;AIM1; AIM2; AIMP1; AIMP2; AIP; AIPL1; AIRE; AJAP1; AJUBA; AK1; AK3; AK6;AK7; AK8; AK9; AKAP10; AKAP12; AKAP13; AKAP17A; AKAP1; AKAP2; AKAP3;AKAP4; AKAP5; AKAP6; AKAP7; AKAP9; AKIP1; AKIRIN2; AKNA; AKR1B10;AKR1B1; AKR1C1; AKR1C2; AKR1C3; AKR1C4; AKR1D1; AKR1E2; AKR7A3; AKT1;AKT1S1; AKT2; AKT3; AKTIP; ALAD; ALAS1; ALAS2; ALB; ALCAM; ALDH16A1;ALDH18A1; ALDH1A1; ALDH1A2; ALDH1A3; ALDH1B1; ALDH1L1; ALDH2; ALDH3A1;ALDH3A2; ALDH3B 1; ALDH4A1; ALDH5A1; ALDH6A1; ALDH7A1; ALDH9A1; ALDOA;ALDOB; ALDOC; ALG10B; ALG10; ALG11; ALG12; ALG13; ALG1; ALG1L; ALG2;ALG3; ALG8; ALG9; ALKBH1; ALKBH2; ALKBH3; ALKBH7; ALKBH8; ALK; ALLC;ALMS1; ALOX12B; ALOX12; ALOX15B; ALOX15; ALOX5AP; ALOX5; ALOXE3; ALPI;ALPK1; ALPK2; ALPK3; ALPP; ALPPL2; ALS 2CL; ALS 2CR12 ; ALS 2 ; ALX1 ;ALX4; ALYREF; AMACR; AMBN; AMBP; AMBRA1; AMD1; AMELX; AMELY; AMER1;AMER2; AMER3; AMFR; AMH; AMHR2; AMICA1; AMIGO2; AMMECR1; AMN; AMOT;AMOTL1; AMPD2; AMPD3; AMPH; AMT; AMZ1; ANAPC10; ANAPC11; ANAPC13;ANAPC1; ANAPC2; ANAPC4; ANAPC5; ANAPC7; ANG; ANGPT1; ANGPT2; ANGPT4;ANGPTL1; ANGPTL2; ANGPTL4; ANGPTL6; ANK1; ANK2; ANK3; ANKFN1; ANKFY1;ANKHD1-EIF4EBP3; ANKHD1; ANKH; ANKK1; ANKLE1; ANKLE2; ANKMY1; ANKRD10;ANKRD11; ANKRD12; ANKRD18A; ANKRD1; ANKRD23; ANKRD26; ANKRD28; ANKRD2;ANKRD30A; ANKRD36B; ANKRD36; ANKRD37; ANKRD44; ANKRD45; ANKRD46;ANKRD50; ANKRD55; ANKRD6; ANKRD7; ANKS1A; ANKS1B; ANKS4B; ANKS6; ANLN;ANO10; ANO1; ANO2; ANO3; ANO4; AND5; ANO6; ANO7; ANP32A; ANP32B; ANP32D;ANPEP; ANTXR1; ANTXR2; ANXA10; ANXA11; ANXA13; ANXA1; ANXA2; ANXA2R;ANXA3; ANXA4; ANXA5; ANXA6; ANXA7; ANXA8; ANXA8L1; AOAH; AOC1; AOC2;AOC3; AOX1; AP1AR; AP1B1; AP1G1; AP1M1; AP1M2; AP1S1; AP1S2; AP1S3;AP2A1; AP2B1; AP2M1; AP2S1; AP3B1; AP3D1; AP3M2; AP3S1; AP3S2; AP4B1;AP4E1; AP4M1; AP4S1; AP5M1; AP5Z1; APAF1; APBA1; APBA2; APBA3; APBB1;APBB1IP; APBB2; APBB3; APC2; APCDD1; APCDD1L; APC; APCS; APEH; APEX1;APEX2; APH1B; API5; APIP; APLN; APLNR; APLP1; APLP2; APOA1BP; APOA2;APOA4; APOA5; APOBEC1; APOBEC2; APOBEC3A_B; APOBEC3B; APOBEC3C;APOBEC3F; APOBEC3G; APOBEC3H; APOB; APOBR; APOC1; APOC2; APOC3; APOC4;APOD; APOE; APOF; APOH; APOL1; APOL2; APOL3; APOL4; APOL6; APOLD1; APOM;APOO; APOPT1; APPBP2; APP; APPL1; APPL2; APRT; APTX; AQP10; AQP1; AQP2;AQP3; AQP4; AQP5; AQP6; AQP7; AQP8; AQP9; ARAF; ARAP1; ARAP3; ARC;ARCN1; AREG; ARF1; ARF3; ARF4; ARF6; ARFGAP1; ARFGAP2; ARFGAP3; ARFGEF1;ARFGEF2; ARFGEF3; ARFIP1; ARFRP1; ARG1; ARGLU1; ARHGAP10; ARHGAP11A;ARHGAP11B; ARHGAP15; ARHGAP18; ARHGAP1; ARHGAP20; ARHGAP21; ARHGAP22;ARHGAP23; ARHGAP24; ARHGAP25; ARHGAP26; ARHGAP27; ARHGAP28; ARHGAP30;ARHGAP31; ARHGAP32; ARHGAP35; ARHGAP42; ARHGAP4; ARHGAP5; ARHGAP6;ARHGAP9; ARHGDIA; ARHGDIB; ARHGEF10; ARHGEF10L; ARHGEF11; ARHGEF12;ARHGEF15; ARHGEF16; ARHGEF17; ARHGEF1; ARHGEF25; ARHGEF26; ARHGEF28;ARHGEF2; ARHGEF38; ARHGEF3; ARHGEF4; ARHGEF5; ARHGEF6; ARHGEF7; ARHGEF9;AR; ARID1B; ARID2; ARID3A; ARID3B; ARID4A; ARID4B; ARID5B; ARIH1; ARL11;ARL13A; ARL13B; ARL14EP; ARL14; ARL15; ARL1; ARL2BP; ARL2; ARL3; ARL4A;ARL4C; ARL4D; ARL5A; ARL5B; ARL6; ARL6IP1; ARL6IP5; ARMC10; ARMC1;ARMC2; ARMC3; ARMC4; ARMC5; ARMC8; ARMC9; ARMCX1; ARMS2; ARMT1; ARNT2;ARNT; ARNTL2; ARNTL; ARPC1A; ARPC1B; ARPC2; ARPC3; ARPC5; ARPIN; ARPP21;ARR3; ARRB1; ARRB2; ARRDC2; ARRDC3; ARRDC4; ARSA; ARSB; ARSD; ARSE;ARSF; ARSG; ARSH; ARSI; ARSJ; ARSK; ART1; ART3; ART4; ARVCF; ARX; AS3MT;ASAH1; ASAH2; ASAP1; ASAP2; ASB10; ASB13; ASB15; ASB18; ASB1; ASB2;ASB6; ASB7; ASCC1; ASCC2; ASCC3; ASCL1; ASCL2; ASCL4; ASF1A; ASF1B;ASH1L; ASH2L; ASIC1; ASIC2; ASIC3; ASIC4; ASIC5; ASIP; ASL; ASMT; ASMTL;ASNA1; ASNS; ASPA; ASPG; ASPH; ASPM; ASPN; ASPRV1; ASPSCR1; ASRGL1;ASS1; ASTN2; ASUN; ASXL1; ASXL2; ASXL3; ASZ1; ATAD2; ATAD3B; ATAD3C;ATAD5; ATAT1; ATCAY; ATE1; ATF1; ATF2; ATF3; ATF4; ATF5; ATF6B; ATF6;ATF7; ATF7IP; ATG10; ATG12; ATG16L1; ATG2B; ATG3; ATG4A; ATG4B; ATG4C;ATG5; ATG7; ATG9A; ATIC; ATL1; ATL2; ATL3; ATM; ATN1; ATOH1; ATOH7;ATOX1; ATP10A; ATP10B; ATP10D; ATP11A; ATP11AUN; ATP11B; ATP12A;ATP13A3; ATP13A4; ATP1A2; ATP1A3; ATP1A4; ATP1B1; ATP1B2; ATP2A1;ATP2A2; ATP2A3; ATP2B1; ATP2B2; ATP2B3; ATP2B4; ATP2C1; ATP2C2; ATP4A;ATP4B; ATP5A1; ATP5B; ATP5C1; ATP5D; ATP5E; ATP5G1; ATP5G2; ATP5G3;ATP5H; ATP5J2; ATP5J; ATP5L; ATP5O; ATP6AP1; ATP6AP1L; ATP6AP2;ATP6V0A1; ATP6V0A2; ATP6V0A4; ATP6V0C; ATP6V0D1; ATP6V0E1; ATP6V0E2;ATP6V1B1; ATP6V1B2; ATP6V1C1; ATP6V1D; ATP6V1E1; ATP6V1F; ATP6V1G1;ATP6V1G2; ATP6V1G3; ATP7A; ATP7B; ATP8A1; ATP8A2; ATP8B1; ATP8B3;ATP8B4; ATP9B; ATPAF2; ATRAID; ATR; ATRIP; ATRN; ATRNL1; ATRX; ATXN10;ATXN1; ATXN1L; ATXN2; ATXN2L; ATXN3; ATXN7; ATXN7L3B; AUH; AURKA; AURKB;AURKC; AUTS2; AVEN; AVP; AVPI1; AVPR1A; AVPR1B; AVPR2; AWAT1; AXDND1;AXIN1; AXIN2; AXL; AZGP1; AZI2; AZIN1; AZIN2; AZU1; B2M; B3GALNT1;B3GALNT2; B3GALT2; B3GALT4; B3GALT5; B3GALTL; B3GAT1; B3GAT2; B3GAT3;B3GNT2; B3GNT3; B3GNT5; B3GNT6; B3GNT8; B3GNTL1; B4GALNT1; B4GALNT2;B4GALNT3; B4GALT1; B4GALT3; B4GALT4; B4GALT5; B4GALT6; B4GALT7; B4GAT1;B9D1; B9D2; BAALC; BAAT; BABAM1; BACE1; BACE2; BACH1; BACH2; BAD; BAG1;BAG3; BAG4; BAG5; BAG6; BAIAP2L1; BAIAP3; BAK1; BAMBI; BANF1; BANK1;BANP; BAP1; BARD1; BARHL1; BARX1; BARX2; BASP1; BATF2; BATF; BAX; BAZ1A;BAZ1B; BAZ2A; BAZ2B; BBC3; BBIP1; BBOX1; BBS10; BBS12; BBS1; BBS2; BBS4;BBS5; BBS7; BBS9; BBX; BCAM; BCAN; BCAP29; BCAP31; BCAR1; BCAS1; BCAS3;BCAS4; BCAT1; BCAT2; BCCIP; BCDIN3D; BCHE; BCKDHA; BCKDHB; BCKDK; BCL10;BCL11A; BCL11B; BCL2A1; BCL2; BCL2L10; BCL2L11; BCL2L12; BCL2L13;BCL2L14; BCL2L1; BCL2L2; BCL2L2-PABPN1; BCL3; BCL6B; BCL6; BCL7A; BCL7B;BCL7C; BCL9L; BCLAF1; BCO1; BCO2; BCOR; BCORL1; BCR; BCS1L; BDH1; BDH2;BDKRB1; BDKRB2; BDNF; BDP1; BEAN1; BEGAIN; BEND3; BEND4; BEST1; BEST2;BET1; BET1L; BEX1; BEX2; BEX4; BFAR; BFSP1; BFSP2; BGLAP; BGN; BHLHA15;BHLHA9; BHLHB9; BHLHE22; BHLHE23; BHLHE40; BHLHE41; BHMT2; BHMT; BICC1;BICD1; BICD2; BID; BIN1; BIN2; BIN3; BIRC2; BIRC3; BIRC5; BIRC6; BIRC7;BIVM; BLCAP; BLID; BLK; BLMH; BLM; BLNK; BLOC1S2; BLOC1S3; BLOC1S4;BLOC1S5; BLOC1S6; BLVRA; BLVRB; BLZF1; BMF; BMI1; BMP10; BMP15; BMP1;BMP2; BMP2K; BMP3; BMP4; BMP5; BMP6; BMP7; BMP8B; BMPER; BMPR1A; BMPR1B;BMPR2; BMS1; BMX; BNC1; BNC2; BNIP1; BNIP2; BNIP3; BNIP3L; BNIPL; BOC;BOD1L2; BOK; BOLA3; BOLL; BOP1; BORA; BPGM; BPIFA1; BPIFA2; BPIFA3;BPIFB1; BPIFB2; BPIFC; BPI; BPNT1; BPTF; BPY2; BRAF; BRAP; BRAT1; BRCA1;BRCA2; BRCC3; BRD1; BRD2; BRD3; BRD4; BRD7; BRD8; BRE; BRF1; BRF2;BRI3BP; BRI3; BRINP1; BRINP2; BRINP3; BRIP1; BRK1; BRMS1; BRMS1L; BRS3;BRSK1; BRSK2; BRWD1; BRWD3; BSCL2; BSG; BSN; BSPH1; BSPRY; BST1; BST2;BSX; BTBD10; BTBD11; BTBD16; BTBD1; BTBD2; BTBD3; BTBD9; BTC; BTD; BTF3;BTG1; BTG2; BTG3; BTG4; BTK; BTLA; BTN1A1; BTN2A1; BTN2A2; BTN3A1;BTN3A2; BTN3A3; BTNL2; BTRC; BUB1B; BUB1; BUB3; BUD13; BUD31; BVES;BYSL; BZRAP1; BZW1; C10orf107; C10orf10; C10orf113; C10orf11; C10orf2;C10orf32; C10orf35; C10orf54; C10orf67; C10orf82; C10orf88; C10orf90;C11orf21; C11orf30; C11orf53; C11orf65; C11orf68; C11orf73; C11orf74;C11orf80; C11orf87; C11orf95; C12orf10; C12orf42; C12orf43; C12orf50;C12orf57; C12orf5; C12orf65; C12orf66; C12orf75; C12orf77; C14orf166;C14orf177; C14orf1; C15orf32; C15orf41; C15orf48; C15orf53; C15orf59;C16orf72; C16orf74; C16orf78; C16orf95; C17orf51; C17orf53; C17orf64;C17orf96; C18orf54; C18orf8; C19orf12; C19orf18; C19orf24; C19orf26;C19orf33; C19orf40; C19orf45; C19orf48; C19orf57; C19orf68; C1D;C1GALT1C1; C1GALT1; C1orf106; C1orf109; C1orf110; C1orf112; C1orf115;C1orf127; C1orf141; C1orf167; C1orf204; C1orf226; C1orf228; C1orf27;C1orf61; C1orf86; C1QB; C1QBP; C1QL1; C1QL3; C1QTNF1; C1QTNF3; C1QTNF5;C1QTNF6; C1QTNF7; C1QTNF9B-AS1; C1R; C1RL; C 1S; C20orf194; C20orf196;C20orf27; C20orf85; C21orf2; C21orf33; C21orf59; C21orf62; C21orf91;C22orf29; C2CD3; C2CD4A; C2CD4B; C2CD5; C2; C2orf16; C2orf40; C2orf43;C2orf47; C2orf57; C2orf61; C3AR1; C3; C3orf17; C3orf18; C3orf20;C3orf35; C3orf56; C3orf58; C3orf67; C3orf79; C4A; C4B_2; C4B; C4BPA;C4BPB; C4orf22; C4orf26; C4orf27; C4orf32; C4orf33; C4orf36; C4orf48;C4orf51; C5AR1; C5AR2; C5; C5orf22; C5orf30; C5orf34; C5orf38; C5orf42;C5orf63; C6; C6orf106; C6orf10; C6orf15; C6orf25; C6orf47; C6orf48;C6orf89; C7; C7orf49; C7orf57; C7orf60; C7orf62; C7orf65; C7orf69;C7orf72; C8orf34; C8orf37; C8orf46; C8orf48; C8orf4; C8orf86; C9;C9orf106; C9orf135; C9orf152; C9orf156; C9orf170; C9orf171; C9orf3;C9orf43; C9orf66; C9orf72; C9orf85; C9orf91; C9orf9; CA10; CA11; CA12;CA13; CA1; CA2; CA3; CA4; CASA; CA6; CA8; CAB39; CAB39L; CABIN1;CABLES1; CABP2; CABP4; CABS1; CABYR; CACNA1A; CACNA1B; CACNA1C; CACNA1D;CACNA1E; CACNA1F; CACNA1G; CACNA1H; CACNA1I; CACNA1S; CACNA2D1;CACNA2D2; CACNA2D3; CACNA2D4; CACNB1; CACNB2; CACNB3; CACNB4; CACNG2;CACNG3; CACNG4; CACNG5; CACNG6; CACUL1; CACYBP; CAD; CADM1; CADM2;CADM3; CADM4; CADPS2; CADPS; CAGE1; CALB1; CALB2; CALCA; CALCB;CALCOCO1; CALCOCO2; CALCR; CALCRL; CALD1; CALHM1; CALHM2; CALHM3; CALM2;CALML3; CALML5; CALN1; CALR3; CALR; CALU; CALY; CAMK1D; CAMK1G; CAMK1;CAMK2A; CAMK2B; CAMK2D; CAMK2G; CAMK4; CAMKK1; CAMKK2; CAMKMT; CAMLG;CAMP; CAMSAP1; CAMSAP2; CAMTA1; CAND1; CAND2; CANT1; CANX; CAP1; CAP2;CAPG; CAPN10; CAPN13; CAPN14; CAPN1; CAPN2; CAPN3; CAPN5; CAPN6; CAPN7;CAPN9; CAPNS1; CAPRIN1; CAPRIN2; CAPS2; CAPS; CAPSL; CAPZA2; CAPZA3;CARD10; CARD11; CARD14; CARD16; CARD6; CARD8; CARDS; CARF; CARKD; CARM1;CARS; CARTPT; CASC1; CASC3; CASC4; CASC5; CASD1; CASK; CASP10; CASP14;CASP1; CASP2; CASP3; CASP4; CASP5; CASP6; CASP7; CASP8AP2; CASP8; CASP9;CASQ1; CASR; CASS4; CAST; CASZ1; CAT; CATSPER1; CATSPER2; CAV1; CAV2;CAV3; CBFA2T2; CBFA2T3; CBFB; CBLB; CBL; CBLL1; CBLN1; CBLN2; CBLN4;CBR1; CBR3; CBR4; CBS; CBX1; CBX2; CBX3; CBX4; CBX5; CBX6; CBX7; CBX8;CBY1; CC2D1A; CC2D1B; CC2D2A; CCAR1; CCAR2; CCBE1; CCBL1; CCDC101;CCDC102B; CCDC103; CCDC105; CCDC108; CCDC114; CCDC115; CCDC121; CCDC122;CCDC129; CCDC130; CCDC134; CCDC136; CCDC140; CCDC141; CCDC148; CCDC151;CCDC167; CCDC169-SOHLH2; CCDC170; CCDC171; CCDC175; CCDC176; CCDC178;CCDC180; CCDC181; CCDC185; CCDC22; CCDC28A; CCDC39; CCDC3; CCDC40;CCDC42B; CCDC42; CCDC50; CCDC54; CCDC60; CCDC62; CCDC63; CCDC65; CCDC66;CCDC67; CCDC68; CCDC6; CCDC78; CCDC80; CCDC83; CCDC85A; CCDC86; CCDC88A;CCDC88C; CCDC8; CCDC91; CCDC94; CCDC97; CCHCR1; CCKAR; CCKBR; CCK;CCL11; CCL13; CCL14; CCL15; CCL16; CCL17; CCL18; CCL19; CCL1; CCL20;CCL21; CCL22; CCL23; CCL24; CCL25; CCL26; CCL27; CCL28; CCL2; CCL3;CCL3L3; CCL4; CCL4L1; CCL4L2; CCL5; CCL7; CCL8; CCM2; CCNA1; CCNA2;CCNB1; CCNB2; CCNB3; CCNC; CCND1; CCND2; CCND3; CCNDBP1; CCNE1; CCNE2;CCNF; CCNG1; CCNG2; CCNH; CCNI; CCNJ; CCNJL; CCNK; CCNL1; CCNL2; CCNO;CCNT1; CCNY; CCP110; CCR10; CCR1; CCR2; CCR3; CCR4; CCR5; CCR6; CCR7;CCR8; CCR9; CCRL2; CCRN4L; CCSER1; CCS; CCT2; CCT3; CCT4; CCT5; CCT6A;CCT6B; CCT7; CD109; CD14; CD151; CD163; CD163L1; CD164; CD177; CD180;CD19; CD1A; CD1B; CD1C; CD1D; CD1E; CD200; CD200R1; CD207; CD209; CD226;CD22; CD244; CD247; CD248; CD24; CD274; CD276; CD27; CD28; CD2AP;CD300A; CD300C; CD300LF; CD302; CD320; CD33; CD34; CD36; CD37; CD38;CD3D; CD3EAP; CD3E; CD3G; CD40; CD40LG; CD44; CD46; CD47; CD48; CD4;CD55; CD59; CD5; CD5L; CD63; CD68; CD69; CD6; CD72; CD74; CD79A; CD79B;CD7; CD80; CD81; CD82; CD83; CD84; CD86; CD8A; CD8B; CD93; CD96; CD99;CD9; CDADC1; CDAN1; CDC123; CDC14A; CDC14B; CDC16; CDC20B; CDC23;CDC25A; CDC25B; CDC25C; CDC27; CDC34; CDC37; CDC37L1; CDC42BPA;CDC42BPB; CDC42BPG; CDC42EP1; CDC42EP3; CDC42SE2; CDC45; CDC5L; CDC6;CDC73; CDC7; CDCA2; CDCA3; CDCA5; CDCA7; CDCA7L; CDCP1; CDH10; CDH11;CDH13; CDH15; CDH16; CDH17; CDH18; CDH19; CDH1; CDH20; CDH22; CDH23;CDH26; CDH2; CDH3; CDH4; CDH5; CDH6; CDH7; CDH8; CDH9; CDHR1; CDHR2;CDHR3; CDHR5; CDIPT; CDK10; CDK11B; CDK12; CDK13; CDK14; CDK15; CDK16;CDK17; CDK18; CDK19; CDK1; CDK20; CDK2AP1; CDK2AP2; CDK2; CDK3; CDK4;CDK5; CDK5R1; CDK5R2; CDK5RAP1; CDK5RAP2; CDK5RAP3; CDK6; CDK7; CDK8;CDK9; CDKAL1; CDKL1; CDKL2; CDKL3; CDKL4; CDKL5; CDKN1A; CDKN1B; CDKN1C;CDKN2A; CDKN2AIP; CDKN2B; CDKN2C; CDKN2D; CDKN3; CDNF; CDO1; CDON; CDR1;CDR2; CDS2; CDT1; CDV3; CDX1; CDX2; CDX4; CDY1B; CDY2B; CDYL2; CDYL;CEACAM16; CEACAM19; CEACAM1; CEACAM21; CEACAM3; CEACAM4; CEACAM5;CEACAM6; CEACAM7; CEACAM8; CEBPA; CEBPB; CEBPD; CEBPE; CEBPG; CEBPZ;CECR1; CECR2; CELA1; CELA3B; CELF1; CELF2; CELF4; CELF5; CELF6; CEL;CELSR1; CELSR3; CEMIP; CEMP1; CEND1; CENPA; CENPB; CENPC; CENPE; CENPF;CENPH; CENPJ; CENPK; CENPN; CENPO; CENPQ; CENPU; CENPV; CENPW; CEP112;CEP120; CEP128; CEP131; CEP135; CEP152; CEP162; CEP164; CEP170; CEP192;CEP19; CEP250; CEP290; CEP41; CEP55; CEP57; CEP63; CEP68; CEP72; CEP76;CEP83; CEP85L; CEP89; CER1; CERK; CERKL; CERS1; CERS2; CERS3; CERS4;CERS6; CES1; CES2; CES3; CETN1; CETN2; CETN3; CETP; CFAP126; CFAP36;CFAP44; CFAP52; CFAP53; CFAP57; CFAP58; CFAP61; CFAP69; CFAP97; CFB;CFC1B; CFC1; CFD; CFDP1; CFH; CFHR1; CFHR2; CFHR3; CFHR4; CFHR5; CFI;CFL1; CFL2; CFLAR; CFP; CFTR; CGA; CGB1; CGB2; CGB5; CGB7; CGN; CGNL1;CGRRF1; CH25H; CHAC1; CHAD; CHAF1A; CHAF1B; CHAMP1; CHAT; CHCHD10;CHCHD1; CHCHD3; CHCHD5; CHCHD6; CHCHD7; CHD1; CHD2; CHD3; CHD4; CHD6;CHD7; CHD8; CHDH; CHEK1; CHEK2; CHERP; CHFR; CHGA; CHGB; CHI3L1; CHIC1;CHIC2; CHIT1; CHKA; CHKB; CHL1; CHM; CHML; CHMP1A; CHMP1B; CHMP2B;CHMP3; CHMP4A; CHMP4B; CHMP4C; CHMP5; CHN1; CHN2; CHODL; CHORDC1; CHP1;CHP2; CHPF; CHPT1; CHRAC1; CHRD; CHRDL1; CHRFAM7A; CHRM1; CHRM2; CHRM3;CHRM4; CHRM5; CHRNA10; CHRNA1; CHRNA2; CHRNA3; CHRNA4; CHRNA5; CHRNA6;CHRNA7; CHRNB 1; CHRNB2; CHRNB3; CHRNB4; CHRND; CHRNE; CHRNG; CHST10;CHST11; CHST12; CHST13; CHST14; CHST15; CHST1; CHST2; CHST3; CHST4;CHST5; CHST6; CHST8; CHST9; CHSY1; CHSY3; CHTF18; CHTOP; CHURC1; CIAO1;CIAPIN1; CIB1; CIB2; CIC; CIDEB; CIDEC; CIITA; CILP2; CILP; CINP; CIPC;CIR1; CIRBP; CIRH1A; CISD1; CISD2; CISH; CITED1; CITED2; CIT; CIZ1;CKAP2; CKAP2L; CKAP4; CKAP5; CKB; CKLF; CKM; CKMT1A; CKMT1B; CKMT2;CKS1B; CKS2; CLASP1; CLASP2; CLCA2; CLCA4; CLCF1; CLC; CLCN1; CLCN2;CLCN3; CLCN4; CLCN5; CLCN6; CLCN7; CLCNKB; CLDN10; CLDN11; CLDN14;CLDN15; CLDN16; CLDN18; CLDN1; CLDN23; CLDN2; CLDN5; CLDN6; CLDN7;CLDN8; CLDN9; CLEC10A; CLEC11A; CLEC12A; CLEC14A; CLEC16A; CLEC1B;CLEC2A; CLEC2B; CLEC2D; CLEC2L; CLEC3B; CLEC4A; CLEC4C; CLEC4D; CLEC4E;CLEC4G; CLEC4M; CLEC5A; CLEC6A; CLEC7A; CLEC9A; CLECL1; CLGN; CLIC1;CLIC3; CLIC5; CLIC6; CLINT1; CLIP1; CLIP2; CLK1; CLK2; CLLU1; CLMN;CLMP; CLN3; CLN5; CLN6; CLN8; CLNK; CLNS1A; CLOCK; CLP1; CLPP; CLPS;CLPTM1; CLPTM1L; CLRN1; CLSPN; CLSTN1; CLSTN2; CLTA; CLTC; CLTCL1;CLUAP1; CLU; CLUL1; CLVS1; CLYBL; CMA1; CMAS; CMC1; CMC2; CMC4; CMIP;CMKLR1; CMPK2; CMSS1; CMTM3; CMTM5; CMTM7; CMTM8; CMTR1; CMTR2; CMYA5;CNBD1; CNBP; CNDP1; CNDP2; CNGA1; CNGA3; CNGB1; CNGB3; CNIH3; CNKSR1;CNKSR2; CNKSR3; CNN1; CNN2; CNNM1; CNNM2; CNNM4; CNOT1; CNOT2; CNOT3;CNOT4; CNOT6; CNOT6L; CNOT7; CNOT8; CNP; CNPY2; CNPY3; CNR1; CNR2;CNRIP1; CNST; CNTF; CNTFR; CNTLN; CNTN1; CNTN2; CNTN3; CNTN4; CNTN5;CNTN6; CNTNAP1; CNTNAP2; CNTNAP3; CNTNAP4; CNTNAP5; CNTRL; CNTROB; COA1;COA5; COASY; COBL; COBLL1; COCH; COG1; COG2; COG3; COG4; COG5; COG6;COG7; COG8; COIL; COL10A1; COL11A1; COL11A2; COL12A1; COL13A1; COL14A1;COL15A1; COL16A1; COL17A1; COL18A1; COL1A1; COL1A2; COL20A1; COL21A1;COL22A1; COL23A1; COL24A1; COL25A1; COL26A1; COL27A1; COL28A1; COL2A1;COL3A1; COL4A1; COL4A2; COL4A3BP; COL4A3; COL4A4; COL4A5; COL4A6;COL5A1; COL5A2; COL5A3; COL6A1; COL6A2; COL6A3; COL6A5; COL7A1; COL8A1;COL8A2; COL9A1; COL9A2; COL9A3; COLCA1; COLCA2; COLEC10; COLEC11;COLEC12; COLGALT2; COLQ; COMMD10; COMMD1; COMMD3-BMI1; COMMD5; COMMD7;COMP; COMT; COPA; COPB1; COPB2; COPE; COPG2; COPRS; COPS2; COPS3; COPS4;COPS5; COPS6; COPS7A; COPS8; COPZ2; COQ2; COQ3; COQ4; COQ5; COQ6; COQ7;COQ9; CORIN; CORO1A; CORO1B; CORO1C; CORO2A; CORO2B; CORO6; CORO7;CORO7-PAM16; COTL1; COX10; COX11; COX14; COX15; COX16; COX17; COX18;COX19; COX4I1; COX4I2; COX5A; COX5B; COX6A1; COX6A2; COX6B1; COX6C;COX7A1; COX7A2; COX7A2L; COX7B2; COX7B; COX7C; COX8A; CPA1; CPA2; CPA3;CPA4; CPA6; CPAMD8; CPB1; CPB2; CPD; CPEB1; CPEB3; CPEB4; CPED1; CPE;CP; CPLX1; CPLX2; CPLX3; CPLX4; CPM; CPN1; CPN2; CPNE1; CPNE2; CPNE3;CPNE4; CPNE7; CPNE8; CPO; CPDX; CPPED1; CPQ; CPS1; CPSF1; CPSF2; CPSF3;CPSF3L; CPSF4; CPSF6; CPSF7; CPT1A; CPT1B; CPT1C; CPVL; CPXCR1; CPZ;CR1; CR2; CRABP1; CRABP2; CRACR2A; CRADD; CRAMP1L; CRAT; CRB1; CRB2;CRB3; CRBN; CRCP; CRCT1; CREB1; CREB3; CREB3L1; CREB3L2; CREB3L3;CREB3L4; CREB5; CREBBP; CREBRF; CREBZF; CREG1; CRELD1; CRELD2; CREM;CRHBP; CRH; CRHR1; CRHR2; CRIM1; CRIP2; CRIP3; CRIPAK; CRIPT; CRISP1;CRISP2; CRISP3; CRISPLD1; CRISPLD2; CRK; CRKL; CRLF1; CRLF2; CRLF3;CRLS1; CRMP1; CRNKL1; CRNN; CROCC; CROT; CRP; CRTAC1; CRTAM; CRTAP;CRTC1; CRTC2; CRTC3; CRX; CRY1; CRY2; CRYAB; CRYBA1; CRYBA2; CRYBA4;CRYBB1; CRYBB2; CRYBB3; CRYGB; CRYGC; CRYGD; CRYGS; CRYL1; CRYM; CRYZL1;CSAD; CSAG3; CSE1L; CSF1R; CSF2; CSF2RA; CSF2RB; CSF3; CSGALNACT1;CSGALNACT2; CSH1; CSH2; CSHL1; CS; CSK; CSMD1; CSMD2; CSMD3; CSN1S1;CSN2; CSN3; CSNK1A1; CSNK1D; CSNK1G3; CSNK2A1; CSNK2A2; CSNK2B; CSPG4;CSPG5; CSPP1; CSRNP1; CSRNP3; CSRP1; CSRP2BP; CSRP2; CSRP3; CST1; CST2;CST3; CST4; CST5; CST6; CST7; CST8; CST9; CST9L; CSTA; CSTB; CSTF1;CSTF2; CSTF2T; CSTL1; CT45A1; CT55; CT83; CTAG1A; CTAG2; CTAGE1; CTAGE5;CTBP1; CTBP2; CTC1; CTCF; CTCFL; CTOP1; CTDSP1; CTDSP2; CTDSPL; CTF1;CTGF; CTHRC1; CTIF; CTLA4; CTNNA1; CTNNA2; CTNNA3; CTNNAL1; CTNNB 1;CTNNBL1; CTNND1; CTNND2; CTNS; CTPS1; CTR9; CTRB1; CTRB2; CTRC; CTRL;CTSA; CTSB; CTSC; CTSD; CTSE; CTSF; CTSG; CTSH; CTSL; CTSO; CTSV; CTSW;CTSZ; CTTNBP2; CTTN; CTU1; CTXN3; CUBN; CUEDC1; CUEDC2; CUL1; CUL2;CUL3; CUL4A; CUL4B; CUL5; CULT; CUL9; CUTA; CUX1; CUX2; CUZD1; CWC22;CWC27; CWF19L1; CWF19L2; CWH43; CX3CL1; CX3CR1; CXADR; CXCL10; CXCL11;CXCL12; CXCL13; CXCL14; CXCL16; CXCL17; CXCL1; CXCL2; CXCL3; CXCL5;CXCL6; CXCL8; CXCL9; CXCR1; CXCR2; CXCR3; CXCR4; CXCR5; CXCR6; CXorf36;CXorf66; CXorf67; CXXC1; CXXC4; CYB561D2; CYB561; CYB5A; CYB5B; CYB5R3;CYB5R4; CYBA; CYBB; CYBRD1; CYC1; CYCS; CYFIP1; CYFIP2; CYGB; CYLC1;CYLC2; CYLD; CYP11A1; CYP11B1; CYP11B2; CYP17A1; CYP19A1; CYP1A1;CYP1A2; CYP1B1; CYP21A2; CYP24A1; CYP26A1; CYP26B1; CYP26C1; CYP27A1;CYP27B1; CYP27C1; CYP2A13; CYP2A6; CYP2A7; CYP2B6; CYP2C18; CYP2C19;CYP2C8; CYP2C9; CYP2D6; CYP2E1; CYP2F1; CYP2R1; CYP2S1; CYP2U1; CYP2W1;CYP39A1; CYP3A43; CYP3A4; CYP3A5; CYP3A7-CYP3A51P; CYP3A7; CYP46A1;CYP4A11; CYP4B 1; CYP4F11; CYP4F12; CYP4F22; CYP4F2; CYP4F3; CYP4F8;CYP4V2; CYP51A1; CYP7A1; CYP7B 1; CYP8B1; CYS1; CYSLTR1; CYTH1; CYTH3;CYTIP; CYTL1; CYYR1; D2HGDH; DAAM1; DAAM2; DAB2; DAB2IP; DACH1; DACH2;DACT1; DACT2; DACT3; DAD1; DAG1; DAND5; DAOA; DAO; DAP3; DAP; DAPK1;DAPK2; DAPK3; DARS2; DARS; DAW1; DAXX; DAZ1; DAZ2; DAZ3; DAZ4; DAZAP1;DAZAP2; DAZL; DBF4; DBH; DBI; DBN1; DBNL; DBP; DBR1; DBX1; DCAF12;DCAF13; DCAF17; DCAF4; DCAF5; DCAF6; DCAF7; DCAF8; DCANP1; DCBLD1;DCBLD2; DCC; DCDC2C; DCDC2; DCD; DCHS1; DCHS2; DCK; DCLK1; DCLK2; DCLK3;DCLRE1A; DCLRE1C; DCN; DCP1A; DCP1B; DCPS; DCST1; DCST2; DCSTAMP; DCTD;DCT; DCTN1; DCTN2; DCTN3; DCTN4; DCTN5; DCTN6; DCUN1D1; DCX; DCXR;DDAH1; DDAH2; DDB1; DDB2; DDC; DDHD1; DDHD2; DDI1; DDIAS; DDIT3; DDIT4;DDIT4L; DDN; DDO; DDR1; DDR2; DDRGK1; DDT; DDTL; DDX10; DDX11; DDX17;DDX18; DDX19A; DDX1; DDX21; DDX25; DDX27; DDX28; DDX31; DDX39A; DDX39B;DDX3X; DDX3Y; DDX41; DDX42; DDX43; DDX46; DDX4; DDX50; DDX51; DDX52;DDX53; DDX54; DDX56; DDX58; DDX59; DDX5; DDX60; DDX6; DEAF1; DEC1;DECR1; DEDD; DEF6; DEFA1B; DEFA3; DEFA4; DEFA5; DEFA6; DEFB103B;DEFB104B; DEFB105A; DEFB106A; DEFB108B; DEFB112; DEFB125; DEFB126;DEFB1; DEFB4A; DEGS1; DEGS2; DEK; DENND1A; DENND1B; DENND2A; DENND4A;DENR; DEPDC1B; DEPDC5; DEPTOR; DERA; DERL1; DERL2; DERL3; DES; DESI2;DEXI; DFFB; DFNA5; DFNB31; DFNB59; DGAT1; DGAT2; DGCR2; DGCR6L; DGCR8;DGKA; DGKB; DGKD; DGKE; DGKG; DGKH; DGKI; DGKK; DGKQ; DGKZ; DGUOK;DHCR7; DHDH; DHFR; DHFRL1; DHH; DHODH; DHPS; DHRS11; DHRS2; DHRS4;DHRS7C; DHRS9; DHTKD1; DHX15; DHX16; DHX32; DHX34; DHX36; DHX38; DHX40;DHX58; DHX8; DHX9; DIABLO; DIAPH1; DIAPH2; DIAPH3; DICER1; DIDO1; DIEXF;DIP2A; DIP2B; DIP2C; DIRAS1; DIRAS2; DIRC1; DIRC2; DIS3; DIS3L2; DIS3L;DISC1; DISP1; DIXDC1; DKC1; DKK1; DKK2; DKK3; DKK4; DKKL1; DLAT; DLC1;DLD; DLEC1; DLEU7; DLG1; DLG2; DLG3; DLG4; DLG5; DLGAP1; DLGAP2; DLGAP3;DLGAP5; DLK1; DLL1; DLL3; DLL4; DLST; DLX1; DLX2; DLX3; DLX4; DLX5;DLX6; DMBT1; DMC1; DMD; DMGDH; DMKN; DMP1; DMPK; DMRT1; DMRT2; DMRT3;DMRTA1; DMTF1; DMTN; DMWD; DMXL1; DMXL2; DNA2; DNAAF1; DNAAF2; DNAAF3;DNAAF5; DNAH11; DNAH12; DNAH17; DNAH1; DNAH2; DNAH3; DNAH5; DNAH6;DNAH7; DNAH8; DNAH9; DNAI1; DNAI2; DNAJA1; DNAJA2; DNAJA3; DNAJB11;DNAJB13; DNAJB1; DNAJB2; DNAJB5; DNAJB6; DNAJB7; DNAJB 8; DNAJB 9;DNAJC10; DNAJC12; DNAJC13; DNAJC14; DNAJC15; DNAJC18; DNAJC19; DNAJC1;DNAJC27; DNAJC28; DNAJC2; DNAJC3; DNAJC5; DNAJC7; DNAL1; DNASE1;DNASE1L2; DNASE1L3; DNASE2B; DNASE2; DND1; DNER; DNHD1; DNLZ; DNM1;DNM1L; DNM2; DNM3; DNMBP; DNMT1; DNMT3A; DNMT3B; DNMT3L; DNPEP; DNTT;DOC2A; DOC2B; DOCK10; DOCK11; DOCK1; DOCK2; DOCK3; DOCK4; DOCK5; DOCK6;DOCK7; DOCK8; DOCK9; DOHH; DOK1; DOK2; DOK3; DOK4; DOK5; DOK6; DOK7;DOLK; DONSON; DOPEY2; DOT1L; DPAGT1; DPCD; DPCR1; DPEP1; DPEP2; DPEP3;DPF1; DPF3; DPH1; DPH3; DPH6; DPH7; DPM1; DPM2; DPM3; DPP10; DPP3; DPP4;DPP6; DPP7; DPP8; DPP9; DPPA2; DPPA3; DPPA4; DPT; DPY19L2; DPY19L3;DPY30; DPYS; DPYSL2; DPYSL3; DPYSL4; DPYSL5; DRAM1; DRAP1; DRC1; DRD1;DRD2; DRD3; DRD4; DRD5; DRG1; DRGX; DROSHA; DRP2; DSC1; DSC2; DSC3;DSCAM; DSCAML1; DSCC1; DSCR4; DSE; DSEL; DSG1; DSG2; DSG3; DSG4; DSP;DSPP; DST; DSTN; DSTYK; DTD1; DTHD1; DTL; DTNA; DTNB; DTNBP1; DTX1;DTX2; DTX3; DTX4; DTYMK; DUOX1; DUOX2; DUOXA1; DUOXA2; DUPD1; DUS2;DUSP10; DUSP11; DUSP12; DUSP13; DUSP14; DUSP15; DUSP16; DUSP18; DUSP1;DUSP21; DUSP22; DUSP23; DUSP27; DUSP28; DUSP2; DUSP3; DUSP4; DUSP5;DUSP6; DUSP7; DUSP8; DUSP9; DUT; DUX4; DVL2; DVL3; DXO; DYM; DYNAP;DYNC1H1; DYNC1I1; DYNC1I2; DYNC1LI1; DYNC2H1; DYNLL1; DYNLL2; DYNLRB 1;DYNLT1; DYNLT3; DYRK1A; DYRK1B; DYRK2; DYRK3; DYSF; DYX1C1; DZIP1; E2F1;E2F3; E2F4; E2F5; E2F6; E2F7; E2F8; E4F1; EAF1; EAF2; EARS2; EBAG9;EBF1; EBF2; EBF3; EBF4; EBI3; EBP; EBPL; ECD; ECE2; ECEL1; ECHDC1;ECHDC3; ECHS1; ECI1; ECI2; ECSCR; ECSIT; ECT2; EDA2R; EDA; EDARADD;EDAR; EDC4; EDEM1; EDIL3; EDN1; EDN3; EDNRA; EDNRB; EEA1; EED; EEF1A1;EEF1A2; EEF1B2; EEF1D; EEF1E1; EEF1G; EEF2; EEFSEC; EFCAB11; EFCAB1;EFEMP1; EFEMP2; EFHB; EFHC1; EFHC2; EFHD1; EFNA1; EFNA2; EFNA3; EFNA4;EFNA5; EFNB 1; EFNB2; EFNB 3; EFR3A; EFR3B; EFS; EFTUD1; EFTUD2; EGF;EGFL6; EGFL7; EGFL8; EGFLAM; EGFR; EGLN1; EGLN2; EGLN3; EGR1; EGR2;EGR3; EGR4; EHBP1; EHD1; EHD2; EHD3; EHD4; EHF; EHHADH; EHMT1; EHMT2;EI24; EID1; EIF1AD; EIF1AX; EIF1AY; EIF1; EIF2A; EIF2AK1; EIF2AK2;EIF2AK3; EIF2AK4; EIF2B1; EIF2B2; EIF2B3; EIF2B4; EIF2B5; EIF2S1;EIF2S2; EIF2S3; EIF3A; EIF3B; EIF3C; EIF3E; EIF3F; EIF3H; EIF3J; EIF3K;EIF3M; EIF4A1; EIF4A2; EIF4A3; EIF4B; EIF4E2; EIF4E3; EIF4EBP1;EIF4EBP2; EIF4EBP3; EIF4E; EIF4ENIF1; EIF4G1; EIF4G2; EIF4H; EIF5A2;EIF5A; EIF5; EIF6; ELAC1; ELAC2; ELANE; ELAVL1; ELAVL2; ELAVL3; ELAVL4;ELF1; ELF2; ELF3; ELF4; ELF5; ELK1; ELK3; ELK4; ELL2; ELL; ELMO1; ELMO2;ELMOD1; ELMOD2; ELMOD3; ELMSAN1; ELN; ELOF1; ELOVL2; ELOVL4; ELOVL5;ELOVL6; ELOVL7; ELP2; ELP3; ELP4; ELP6; ELSPBP1; EMB; EMC10; EMC2; EMC3;EMC7; EMC8; EMCN; EMD; EME1; EMG1; EMILIN1; EMILIN2; EMILIN3; EML1;EML2; EML4; EML5; EML6; EMP1; EMP2; EMX1; EMX2; EN1; EN2; ENAH; ENAM;ENC1; ENDOG; ENDOU; ENDOV; ENGASE; ENG; ENHO; ENO2; ENO3; ENO4; ENOPH1;ENOSF1; ENOX1; ENOX2; ENPEP; ENPP1; ENPP2; ENPP3; ENPP5; ENPP7; ENTHD2;ENTPD1; ENTPD2; ENTPD4; ENTPD5; ENTPD6; ENTPD7; EOGT; EOMES; EP300;EP400; EPAS1; EPB41L1; EPB41L2; EPB41L3; EPB41L4A; EPB41L4B; EPB42;EPC1; EPC2; EPCAM; EPDR1; EPG5; EPGN; EPHA1; EPHA3; EPHA4; EPHA5; EPHA6;EPHA7; EPHB1; EPHB3; EPHB4; EPHB6; EPHX1; EPHX2; EPHX3; EPM2A; EPM2AIP1;EPN1; EPO; EPOR; EPPIN; EPPIN-WFDC6; EPPK1; EPRS; EPS15L1; EPS8; EPS8L2;EPSTI1; EPX; EPYC; ERAL1; ERAP1; ERAP2; ERAS; ERBB2; ERBB2IP; ERBB3;ERBB4; ERC1; ERC2; ERCC1; ERCC2; ERCC3; ERCC4; ERCC5; ERCC6; ERCC6L2;ERCC6-PGBD3; ERCC8; EREG; ERF; ERG; ERGIC1; ERGIC2; ERGIC3; ERI3;ERICH5; ERICH6B; ERLEC1; ERLIN1; ERLIN2; ERMAP; ERMARD; ERMP1; ERN1;ERN2; ERO1LB; ERO1L; ERP29; ERP44; ERV3-1; ERVW-1; ESAM; ESCO1; ESCO2;ESD; ESF1; ESM1; ESPL1; ESPN; ESR1; ESR2; ESRP1; ESRP2; ESRRA; ESRRB;ESRRG; ESX1; ESYT1; ESYT2; ESYT3; ETAA1; ETF1; ETFA; ETFB; ETFDH; ETHE1;ETNK1; ETNK2; ETNPPL; ETS1; ETS2; ETV1; ETV3; ETV4; ETV5; ETV6; ETV7;EVA1A; EVA1C; EVC2; EVC; EVI2A; EVI2B; EVI5; EVL; EVPL; EVX1; EVX2;EWSR1; EXD2; EXD3; EXO1; EXOC1; EXOC2; EXOC3L1; EXOC3L2; EXOC4; EXOC5;EXOC7; EXOG; EXOSC1; EXOSC2; EXOSC3; EXOSC4; EXOSC5; EXOSC6; EXOSC7;EXOSC8; EXPH5; EXT1; EXT2; EXTL2; EXTL3; EYA1; EYA2; EYA4; EYS; EZH1;EZH2; EZR; F10; F11; F11R; F12; F13A1; F13B; F2; F2R; F2RL1; F2RL2;F2RL3; F5; F7; F8; F9; FA2H; FAAH2; FABP1; FABP2; FABP4; FABP5; FABP6;FABP7; FABP9; FADD; FADS1; FADS2; FADS3; FAF2; FAHD2A; FAH; FAIM2;FAIM3; FAM102A; FAM103A1; FAM105A; FAM107A; FAM107B; FAM109A; FAM110A;FAM110B; FAM110C; FAM111B; FAM114A1; FAM120B; FAM120C; FAM124B; FAM126A;FAM129A; FAM129B; FAM134B; FAM135A; FAM135B; FAM136A; FAM13A; FAM13C;FAM149A; FAM150B; FAM155A; FAM160B1; FAM161A; FAM163A; FAM163B; FAM167A;FAM168A; FAM168B; FAM169B; FAM170A; FAM172A; FAM173B; FAM174A; FAM175A;FAM175B; FAM177A1; FAM177B; FAM178A; FAM178B; FAM179B; FAM180A; FAM184A;FAM184B; FAM187B; FAM188A; FAM188B; FAM189B; FAM193B; FAM196A; FAM196B;FAM198B; FAM19A1; FAM19A2; FAM19A4; FAM19A5; FAM204A; FAM205A; FAM20A;FAM20B; FAM20C; FAM210B; FAM213A; FAM214A; FAM216A; FAM220A; FAM227B;FAM32A; FAM3A; FAM3B; FAM3C; FAM3D; FAM46A; FAM46D; FAM49A; FAM49B;FAM50B; FAM53B; FAM57A; FAM58A; FAM60A; FAM63B; FAM64A; FAM65B; FAM69C;FAM71F1; FAM71F2; FAM72B; FAM78B; FAM81B; FAM83A; FAM83B; FAM83D;FAM83H; FAM84A; FAM84B; FAM89A; FAM92A1; FAM92B; FAM9B; FAN1; FANCA;FANCB; FANCC; FANCD2; FANCE; FANCF; FANCG; FANCI; FANCL; FANCM; FANK1;FAP; FAR1; FARP1; FARP2; FARS2; FARSA; FAS; FASLG; FASN; FASTKD2; FASTK;FAT1; FAT2; FAT3; FAT4; FATE1; FAU; FBF1; FBL; FBLIM1; FBLN1; FBLN2;FBLN5; FBN1; FBN2; FBN3; FBP1; FBP2; FBRS; FBXL15; FBXL17; FBXL19;FBXL20; FBXL2; FBXL3; FBXL4; FBXL5; FBXL7; FBXO10; FBXO11; FBXO15;FBXO17; FBXO18; FBXO28; FBXO30; FBXO31; FBXO32; FBXO33; FBXO38; FBXO3;FBXO40; FBXO47; FBXO4; FBXO5; FBXO7; FBXO8; FBXO9; FBXW11; FBXW4; FBXW7;FBXW8; FCAR; FCER1A; FCER1G; FCER2; FCGBP; FCGR2A; FCGR2B; FCGR3A;FCGR3B; FCGRT; FCHO1; FCHO2; FCHSD2; FCN1; FCN2; FCRL1; FCRL2; FCRL3;FCRL4; FCRL5; FCRL6; FCRLA; FCRLB; FDFT1; FDPS; FDX1; FDX1L; FDXR; FECH;FEM1A; FEM1B; FEM1C; FEN1; FERD3L; FER; FERMT1; FERMT2; FERMT3; FES;FEV; FEZ1; FEZ2; FEZF1; FEZF2; FFAR1; FFAR2; FFAR3; FFAR4; FGA; FGB;FGD1; FGD2; FGD3; FGD4; FGD5; FGD6; FGF10; FGF11; FGF12; FGF13; FGF14;FGF16; FGF17; FGF18; FGF19; FGF1; FGF20; FGF21; FGF23; FGF2; FGF3; FGF4;FGF5; FGF6; FGF7; FGF8; FGF9; FGFBP1; FGFBP2; FGFBP3; FGFR1; FGFR1OP2;FGFR1OP; FGFR2; FGFR3; FGFR4; FGFRL1; FGG; FGGY; FGL1; FGL2; FGR; FHDC1;FH; FHIT; FHL1; FHL2; FHL5; FHOD1; FHOD3; FIBP; FIG4; FIGF; FIGLA; FIGN;FILIP1; FILIP1L; FIP1L1; FIS 1; FITM1; FITM2; FJX1; FKBP10; FKBP11;FKBP14; FKBP15; FKBP1A; FKBP1B; FKBP2; FKBP3; FKBP4; FKBP5; FKBP6;FKBP7; FKBP8; FKBP9; FKBPL; FKRP; FKTN; FLAD1; FLCN; FLG2; FLG; FLI1;FLII; FLNA; FLNB; FLNC; FLOT1; FLOT2; FLRT2; FLRT3; FLT1; FLT3; FLT3LG;FLT4; FLVCR1; FLVCR2; FMN1; FMN2; FMNL1; FMNL2; FMNL3; FMO1; FMO2; FMO3;FMO4; FMOD; FMR1; FN1; FN3K; FN3KRP; FNBP1; FNDC1; FNDC3A; FNDC3B;FNDC4; FNTA; FNTB; FOCAD; FOLH1; FOLR1; FOLR2; FOLR3; FOPNL; FOSB; FOS;FOSL1; FOSL2; FOXA1; FOXA2; FOXA3; FOXB1; FOXC1; FOXC2; FOXD1; FOXE1;FOXF1; FOXF2; FOXG1; FOXH1; FOXI1; FOXJ1; FOXJ2; FOXK1; FOXK2; FOXL1;FOXL2; FOXM1; FOXN1; FOXN2; FOXN3; FOXO1; FOXO3; FOXO4; FOXO6; FOXP1;FOXP2; FOXP3; FOXP4; FOXQ1; FOXR1; FOXR2; FOXRED1; FPGS; FPR1; FPR2;FPR3; FRAS1; FRAT1; FRAT2; FREM1; FREM2; FREM3; FRG1; FRG2; FRK; FRMD3;FRMD4A; FRMD4B; FRMD5; FRMD6; FRMD7; FRMPD1; FRMPD2; FRMPD4; FRRS1L; FRS2; FRS3; FRY; FRYL; FRZB; FSBP; FSCB; FSCN1; FSCN2; FSD1; FSD1L; FSD2;FSHB; FSHR; FSIP1; FST; FSTL1; FSTL3; FSTL4; FSTL5; FTCD; FTH1; FTL;FTMT; FTO; FTSJ1; FTSJ2; FTSJ3; FUBP1; FUBP3; FUCA1; FUCA2; FUNDC1;FUNDC2; FURIN; FUS; FUT10; FUT11; FUT1; FUT2; FUT3; FUT4; FUT5; FUT6;FUT7; FUT8; FUT9; FUZ; FXN; FXR1; FXR2; FXYD1; FXYD2; FXYD3; FXYD5;FXYD6; FYB; FYCO1; FYN; FZD10; FZD1; FZD2; FZD3; FZD4; FZD5; FZD6; FZD7;FZD8; FZD9; FZR1; GOS2; G2E3; G3BP1; G6PC2; G6PC3; G6PC; G6PD; GAA;GAB1; GAB2; GAB3; GABARAP; GABARAPL1; GABARAPL2; GABBR1; GABBR2; GABPA;GABPB1; GABRA1; GABRA2; GABRA3; GABRA4; GABRA5; GABRA6; GABRB1; GABRB2;GABRB3; GABRE; GABRG1; GABRG2; GABRG3; GABRP; GABRQ; GABRR1; GABRR2;GAD1; GAD2; GADD45B; GADD45G; GADD45GIP1; GADL1; GAGE10; GAGE1; GAK;GALL; GAL; GALK1; GALK2; GALM; GALNS; GALNT12; GALNT13; GALNT14;GALNT15; GALNT18; GALNT1; GALNT2; GALNT3; GALNT4; GALNT5; GALNT6;GALNT7; GALNT8; GALNT9; GALNTL6; GALP; GALR1; GALR2; GALR3; GALT; GAMT;GANAB; GANC; GAN; GAP43; GAPDH; GAPDHS; GAR1; GAREM; GARNL3; GARS; GART;GAS1; GAS2; GAS2L1; GAS6; GAS7; GASB; GAST; GATA1; GATA2; GATA3; GATA4;GATA5; GATA6; GATAD1; GATAD2A; GATAD2B; GATB; GATM; GBA2; GBA; GBAS;GBE1; GBF1; GBGT1; GBX1; GBX2; GCA; GCC1; GCDH; GCFC2; GCG; GCGR; GCH1;GCHFR; GC; GCK; GCKR; GCLC; GCM1; GCM2; GCN1L1; GCNT1; GCNT2; GCNT3;GCNT7; GCOM1; GCSAM; GCSAML; GCSH; GDA; GDAP1; GDE1; GDF10; GDF11;GDF15; GDF1; GDF2; GDF3; GDF5; GDF6; GDF7; GDF9; GDI1; GDI2; GDNF;GDPD3; GDPD5; GEM; GEMIN2; GEMIN4; GEMIN6; GEN1; GET4; GFAP; GFER;GFI1B; GFI1; GFM1; GFPT1; GFPT2; GFRA1; GFRA2; GFRA3; GFRA4; GGA1; GGA3;GGACT; GGCT; GGCX; GGH; GGNBP2; GGN; GGPS1; GGT1; GGT2; GGT5; GGTLC1;GH1; GH2; GHITM; GHRH; GHR; GHRHR; GHRL; GHSR; GID8; GIF; GIGYF1;GIGYF2; GIMAP5; GIMAP7; GIMAP8; GIN1; GINS1; GINS2; GIPC1; GIPC3; GIP;GIPR; GIT1; GIT2; GJA1; GJA3; GJA8; GJB1; GJB2; GJB6; GJC1; GJC2; GJC3;GJD2; GJD3; GK; GKN1; GKN2; GLA; GLB1; GLCCI1; GLCE; GLDC; GLDN; GLE1;GLG1; GLI1; GLI2; GLI3; GLIPR1; GLIPR2; GLIS2; GLIS3; GLMN; GLO1; GLOD4;GLP1R; GLP2R; GLRA1; GLRA2; GLRA3; GLRB; GLRX2; GLRX3; GLRX5; GLRX;GLS2; GLS; GLT1D1; GLT6D1; GLT8D1; GLTSCR1; GLTSCR2; GLUD1; GLUD2; GLUL;GLYAT; GLYATL3; GLYCTK; GM2A; GMCL1; GMDS; GMFB; GMFG; GMIP; GML; GMNN;GMPPA; GMPPB; GMPR2; GMPR; GMPS; GNA11; GNA12; GNA13; GNA14; GNA15;GNAI1; GNAI2; GNAL; GNAO1; GNAQ; GNAS; GNAT1; GNAT3; GNAZ; GNB1L;GNB2L1; GNB3; GNB4; GNB5; GNE; GNG10; GNG11; GNG2; GNG4; GNG7; GNG8;GNGT1; GNGT2; GNL1; GNL3; GNL3L; GNLY; GNMT; GNPAT; GNPDA1; GNPDA2;GNPTAB; GNPTG; GNRH1; GNRH2; GNRHR; GNS; GOLGA1; GOLGA2; GOLGA3; GOLGA4;GOLGA5; GOLGA8B; GOLGB1; GOLM1; GOLPH3; GOLT1A; GOLT1B; GON4L; GOPC;GORAB; GORASP1; GORASP2; GOSR1; GOSR2; GOT1; GOT2; GP1BA; GP1BB; GP2;GPS; GP6; GP9; GPA33; GPAA1; GPALPP1; GPAM; GPANK1; GPAT2; GPATCH1;GPATCH2; GPATCH2L; GPATCH8; GPB AR1; GPC1; GPC2; GPC3; GPC4; GPC5; GPC6;GPCPD1; GPD1; GPD1L; GPD2; GPER1; GPHA2; GPHN; GPIHBP1; GPI; GPKOW;GPLD1; GPM6A; GPM6B; GPN1; GPNMB; GPR101; GPR119; GPR12; GPR132; GPR135;GPR137C; GPR139; GPR143; GPR148; GPR149; GPR150; GPR151; GPR152; GPR153;GPR155; GPR156; GPR158; GPR15; GPR160; GPR161; GPR162; GPR171; GPR174;GPR176; GPR179; GPR17; GPR180; GPR182; GPR183; GPR19; GPR1; GPR20;GPR22; GPR26; GPR34; GPR35; GPR37; GPR37L1; GPR39; GPR4; GPR50; GPR52;GPR55; GPR65; GPR68; GPR6; GPR75; GPR78; GPR83; GPR87; GPRAS P1; GPRC5A;GPRC5B; GPRC5C; GPRC5D; GPRC6A; GPRIN1; GPRIN2; GPRIN3; GPS2; GPSM1;GPSM2; GPSM3; GPT2; GPT; GPX5; GRAMD1B; GRAMD3; GRAMD4; GRAP2; GRAP;GRASP; GRB10; GRB14; GRB2; GRB7; GREB1; GREM1; GREM2; GRHL1; GRHL2;GRHPR; GRIA1; GRIA2; GRIA3; GRIA4; GRID1; GRID2; GRIK1; GRIK2; GRIK4;GRIK5; GRIN1; GRIN2A; GRIN2B; GRIN2C; GRIN2D; GRIN3A; GRIN3B; GRINA;GRIP1; GRK1; GRK4; GRK5; GRK6; GRK7; GRM1; GRM2; GRM3; GRM4; GRM5; GRM6;GRM7; GRM8; GRN; GRPEL1; GRP; GRPR; GRSF1; GRXCR1; GRXCR2; GSC2; GSC;GSDMA; GSDMB; GSDMC; GSDMD; GSE1; GSG1L; GSK3A; GSK3B; GSN; GSPT1;GSPT2; GSR; GSS; GSTA1; GSTA2; GSTA4; GSTA5; GSTCD; GSTK1; GSTM3; GSTO1;GSTO2; GSTP1; GSTT1; GSTT2B; GSTT2; GSTZ1; GSX1; GSX2; GTDC1; GTF2A1;GTF2A1L; GTF2A2; GTF2E1; GTF2E2; GTF2F1; GTF2F2; GTF2H1; GTF2H2C2;GTF2H2C; GTF2H2; GTF2H3; GTF2H4; GTF2H5; GTF2I; GTF2IRD1; GTF2IRD2;GTF3A; GTF3C1; GTPBP1; GTPBP3; GTPBP4; GTSF1; GUCA1A; GUCA1B; GUCD1;GUCY1A2; GUCY1A3; GUCY1B3; GUCY2C; GUCY2D; GUCY2F; GUK1; GULP1; GUSB;GYG1; GYG2; GYLTL1B; GYPA; GYPB; GYPC; GYPE; GYS1; GYS2; GZF1; GZMA;GZMB; GZMH; GZMK; GZMM; H1F0; H1FX; H2AFJ; H2AFX; H2AFY2; H2AFY; H2AFZ;H2BFWT; H3F3B; HAAO; HABP2; HABP4; HACD1; HACD2; HACD4; HACE1; HACL1;HADHA; HADHB; HADH; HAGH; HAL; HAMP; HAND1; HAND2; HAO1; HAO2; HAP1;HAPLN1; HAPLN4; HARS2; HARS; HAS1; HAS2; HAS3; HAT1; HAVCR1; HAVCR2;HAX1; HBA2; HBB; HBD; HBE1; HBEGF; HBG1; HBG2; HBM; HBP1; HBQ1; HBS1L;HBZ; HCAR1; HCAR2; HCAR3; HCCS; HCFC1; HCFC2; HCK; HCLS1; HCN1; HCN2;HCN3; HCN4; HCRT; HCRTR2; HCST; HDAC10; HDAC11; HDAC1; HDAC2; HDAC3;HDAC4; HDAC5; HDAC6; HDAC7; HDAC8; HDAC9; HDC; HDDC2; HDGF; HDGFL1;HDGFRP3; HDHD1; HDLBP; HEATR1; HEATR3; HEATR5B; HEATR6; HEBP1; HEBP2;HECA; HECTD2; HECTD4; HECW1; HECW2; HEG1; HELLS; HELQ; HELT; HELZ2;HELZ; HEMGN; HEPACAM; HEPH; HEPN1; HERC1; HERC2; HERC3; HERC5; HERC6;HERPUD1; HES1; HES2; HES 6; HES7; HESX1; HEXA; HEXB; HEXDC; HEXIM1;HEY1; HEY2; HFE; HFM1; HGD; HGFAC; HGF; HGH1; HGS; HGSNAT; HHAT; HHATL;HHEX; HHIP; HHIPL1; HHLA1; HHLA2; HIAT1; HIBADH; HIBCH; HIC1; HIC2;HID1; HIF1A; HIF1AN; HIF3A; HIGD1A; HIGD1C; HIGD2A; HILPDA; HINFP;HINT1; HINT2; HIP1; HIP1R; HIPK1; HIPK2; HIPK3; HIRA; HIRIP3; HIST1H1A;HIST1H1B; HIST1H1C; HIST1H1D; HIST1H1E; HIST1H1T; HIST1H2AE; HIST1H2AH;HIST1H2BG; HIST1H2BH; HIST1H2BM; HIST1H3G; HIST1H4D; HIST3H3; HIVEP1;HIVEP2; HJURP; HK1; HK2; HK3; HKDC1; HLA-A; HLA-B; HLA-C; HLA-DMA;HLA-DMB; HLA-DOA; HLA-DOB; HLA-DPA1; HLA-DPB1; HLA-DQA1; HLA-DQA2;HLA-DQB1; HLA-DQB2; HLA-DRA; HLA-DRB 1; HLA-DRB3; HLA-DRB4; HLA-DRB5;HLA-E; HLA-F; HLA-G; HLCS; HLF; HLTF; HLX; HM13; HMBOX1; HMBS; HMCN1;HMG20A; HMG20B; HMGA1; HMGA2; HMGB1; HMGB2; HMGB3; HMGCR; HMGCS1; HMGN1;HMGN4; HMGN5; HMGXB3; HMGXB4; HMHA1; HMMR; HMOX1; HMOX2; HMP19; HMSD;HMX1; HN1; HN1L; HNF1A; HNF1B; HNF4A; HNF4G; HNMT; HNRNPAO; HNRNPA 1;HNRNPA2B 1; HNRNPA3; HNRNPAB; HNRNPC; HNRNPD; HNRNPDL; HNRNPF; HNRNPH1;HNRNPH2; HNRNPK; HNRNPL; HNRNPM; HNRNPR; HNRNPU; HNRNPUL1; HOGA1;HOMER1; HOMER2; HOMER3; HOMEZ; HOOK2; HOOK3; HOPX; HORMAD2; HOXA10;HOXA11; HOXA13; HOXA1; HOXA2; HOXA3; HOXA4; HOXA5; HOXA6; HOXA7; HOXA9;HOXB13; HOXB1; HOXB2; HOXB3; HOXB4; HOXB5; HOXB6; HOXB7; HOXB8; HOXB9;HOXC10; HOXC11; HOXC12; HOXC13; HOXC4; HOXC5; HOXC6; HOXC8; HOXC9;HOXD10; HOXD11; HOXD12; HOXD13; HOXD1; HOXD3; HOXD4; HOXD8; HOXD9;HP1BP3; HPCAL1; HPD; HPGD; HPGDS; HP; HPN; HPR; HPRT1; HPS1; HPS3; HPS4;HPS5; HPS6; HPSE2; HPSE; HPX; HRAS; HRASLS; HRC; HRG; HRH1; HRH2; HRH3;HRH4; HR; HRK; HRNR; HRSP12; HS1BP3; HS3ST1; HS3ST2; HS3ST3A1; HS3ST3B1;HS3ST4; HS3ST5; HS3ST6; HS6ST1; HS6ST2; HS6ST3; HSBP1; HSD11B1;HSD11B1L; HSD11B2; HSD17B10; HSD17B11; HSD17B12; HSD17B13; HSD17B14;HSD17B1; HSD17B2; HSD17B3; HSD17B4; HSD17B6; HSD17B7; HSD17B8; HSD3B1;HSD3B7; HSDL1; HSDL2; HSF1; HSF2; HSF4; HSF5; HSFY2; HSH2D; HSP90AA1;HSP90AB1; HSP90B1; HSPA12A; HSPA12B; HSPA13; HSPA14; HSPA1A; HSPA1L;HSPA2; HSPA4; HSPA4L; HSPA5; HSPA6; HSPA8; HSPA9; HSPB1; HSPB2; HSPB3;HSPB6; HSPB7; HSPB8; HSPB9; HSPBAP1; HSPBP1; HSPD1; HSPE1; HSPG2; HSPH1;HTATIP2; HTN1; HTN3; HTR1A; HTR1B; HTR1E; HTR1F; HTR2A; HTR2B; HTR2C;HTR3A; HTR3B; HTR3C; HTR3D; HTR3E; HTR4; HTR5A; HTR7; HTRA1; HTRA2;HTRA3; HTRA4; HTT; HUNK; HUS 1B; HUS1; HUWE1; HVCN1; HYAL1; HYAL2;HYAL3; HYAL4; HYDIN; HYKK; HYLS 1; HYOU1; HYPM; IAPP; IARS2; TARS;IBA57; IBSP; IBTK; ICA1; ICAM1; ICAM2; ICAM3; ICAM4; ICAM5; ICE1; ICE2;ICK; ICMT; ICOS; ICOSLG; ID1; ID2; ID4; IDE; IDH1; IDH2; IDH3B; IDNK;IDO1; IDO2; IDS; IDUA; IER2; IER3; IER3IP1; IER5; IFFO1; IFFO2; IFI16;IFI27; IFI30; IFI35; IFI44; IFIH1; IFIT1; IFIT2; IFIT3; IFIT5; IFITM1;IFITM2; IFITM3; IFITM5; IFNA10; IFNA13; IFNA14; IFNA16; IFNA17; IFNA1;IFNA21; IFNA2; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNAR1; IFNAR2; IFNB1;IFNE; IFNG; IFNGR1; IFNGR2; IFNK; IFNL1; IFNL2; IFNL3; IFNW1; IFRD1;IFT122; IFT140; IFT172; IFT27; IFT43; IFT57; IFT74; IFT80; IFT88; IGBP1;IGDCC3; IGF1; IGF1R; IGF2BP1; IGF2BP2; IGF2BP3; IGF2; IGF2R; IGFALS;IGFB P1; IGFB P2; IGFB P3; IGFB P4; IGFB P5; IGFBP6; IGFBP7; IGFBPL1;IGFL1; IGFLR1; IGHMBP2; IGJ; IGLL1; IGSF10; IGSF11; IGSF1; IGSF5; IGSF6;IGSF8; IHH; IKBKAP; IKBKB; IKBKE; IKBKG; IK; IKZF1; IKZF2; IKZF3; IKZF4;IL10; IL10RA; IL10RB; IL11; IL11RA; IL12A; IL12B; IL12RB1; IL13;IL13RA1; IL13RA2; IL15; IL15RA; IL16; IL17A; IL17B; IL17C; IL17D; IL17F;IL17RA; IL17RB; IL17RC; IL17RD; IL17RE; IL17REL; IL18BP; IL18; IL18R1;IL18RAP; IL19; IL1A; IL1B; IL1F10; IL1R1; IL1R2; IL1RAP; IL1RAPL1;IL1RAPL2; IL1RL1; IL1RL2; IL1RN; IL20; IL20RA; IL20RB; IL21; IL21R;IL22; IL22RA2; IL23A; IL23R; IL24; IL25; IL26; IL27; IL27RA; IL2; IL2RA;IL2RB; IL2RG; IL31; IL31RA; IL32; IL33; IL34; IL36A; IL36B; IL36G;IL36RN; IL37; IL3; IL3RA; IL4; IL4I1; IL4R; IL5; IL5RA; IL6; IL6R;IL6ST; IL7; IL7R; IL9; IL9R; ILDR1; ILDR2; ILF2; ILF3; ILK; IMMP1L;IMMP2L; IMMT; IMP3; IMPA1; IMPA2; IMPACT; IMPAD1; IMPDH1; IMPDH2; IMPG1;IMPG2; INADL; INA; INCENP; INF2; ING1; ING2; ING3; ING4; ING5; INHA;INHBA; INHBB; INHBC; INHBE; INO80B; INO80D; INO80; INPP1; INPP4A;INPP4B; INPP5A; INPP5B; INPP5D; INPP5E; INPP5F; INPP5K; INPPL1; INSC;INS; INSIG1; INSIG2; INS-IGF2; INSL3; INSL4; INSL6; INSM1; INSM2; INSR;INSRR; INTS12; INTS1; INTS2; INTS3; INTS4; INTS5; INTS6; INTS7; INTS8;INTU; INVS; IP6K1; IP6K2; IP6K3; IPCEF1; IPMK; IPO11; IPO13; IPO7; IPO8;IPO9; IQCB1; IQCG; IQCH; IQCJ; IQCJ-SCHIP1; IQCK; IQGAP1; IQGAP2;IQGAP3; IQSEC1; IQSEC2; IQSEC3; IRAK1BP1; IRAK1; IRAK2; IRAK3; IRAK4;IREB2; IRF1; IRF2BP2; IRF2BPL; IRF2; IRF3; IRF4; IRF5; IRF6; IRF7; IRF8;IRF9; IRG1; IRGM; IRS1; IRS2; IRS4; IRX1; IRX2; IRX3; IRX4; IRX5; ISCU;ISG20; ISL1; ISM1; ISM2; ISPD; IST1; ISX; ISYNA1; ITCH; ITFG1; ITFG3;ITGA10; ITGA11; ITGA1; ITGA2B; ITGA2; ITGA3; ITGA4; ITGA5; ITGA6; ITGA7;ITGA8; ITGA9; ITGAD; ITGAE; ITGAL; ITGAM; ITGAV; ITGAX; ITGB1BP1; ITGB1;ITGB2; ITGB3; ITGB4; ITGB5; ITGB6; ITGB7; ITGB8; ITGBL1; ITIH1; ITIH2;ITIH3; ITIH4; ITIH5; ITK; ITLN1; ITLN2; ITM2A; ITM2B; ITM2C; ITPA;ITPK1; ITPKA; ITPKC; ITPR1; ITPR2; ITPR3; ITSN1; ITSN2; IVD; IVL;IVNS1ABP; IYD; IZUMO1; JADE1; JADE2; JAG1; JAG2; JAGN1; JAK2; JAK3;JAKMIP1; JAKMIP2; JAKMIP3; JAM2; JAM3; JARID2; JAZF1; JDP2; JMJD1C;JMJD6; JMY; JPH2; JPH3; JPH4; JRK; JSRP1; JTB; JUNB; JUND; JUP; KAL1;KALRN; KANK1; KANK2; KANK4; KANSL1; KANSL3; KARS; KAT2A; KAT2B; KAT5;KAT6A; KAT6B; KAT7; KATE; KATNA1; KATNAL2; KATNB 1; KAZALD1; KAZN;KBTBD11; KBTBD13; KBTBD8; KCMF1; KCNA1; KCNA4; KCNA5; KCNA6; KCNA7;KCNAB1; KCNAB2; KCNAB3; KCNB1; KCNB2; KCNC1; KCNC2; KCNC3; KCND2; KCNE1;KCNE2; KCNE3; KCNE4; KCNE5; KCNG3; KCNG4; KCNH1; KCNH2; KCNH3; KCNH4;KCNH5; KCNH6; KCNH7; KCNH8; KCNIP1; KCNIP2; KCNIP3; KCNIP4; KCNJ10;KCNJ11; KCNJ12; KCNJ13; KCNJ14; KCNJ15; KCNJ16; KCNJ18; KCNJ1; KCND2;KCNJ3; KCNJ4; KCNJ5; KCNJ6; KCNJ8; KCNJ9; KCNK10; KCNK12; KCNK16;KCNK17; KCNK18; KCNK1; KCNK2; KCNK3; KCNK5; KCNK6; KCNK9; KCNMA1;KCNMB1; KCNMB2; KCNMB3; KCNMB4; KCNN1; KCNN2; KCNN3; KCNN4; KCNQ1;KCNQ2; KCNQ3; KCNQ5; KCNRG; KCNS1; KCNS3; KCNT1; KCNT2; KCNU1; KCNV1;KCNV2; KCTD10; KCTD11; KCTD12; KCTD13; KCTD15; KCTD16; KCTD1; KCTD21;KCTD2; KCTD3; KCTD6; KCTD7; KCTD9; KDELC1; KDELR1; KDM2A; KDM2B; KDM3A;KDM3B; KDM4B; KDM4C; KDMSA; KDMSB; KDMSC; KDMSD; KDM6A; KDM6B; KDR;KDSR; KEAP1; KEL; KERA; KHDC3L; KHDRBS2; KHDRBS3; KHK; KHSRP; KIAA0020;KIAA0040; KIAA0100; KIAA0101; KIAA0196; KIAA0226; KIAA0226L; KIAA0232;KIAA0319; KIAA0319L; KIAA0355; KIAA0391; KIAA0586; KIAA0825; KIAA0907;KIAA0922; KIAA1024; KIAA1033; KIAA1109; KIAA1147; KIAA1161; KIAA1211;KIAA1211L; KIAA1217; KIAA1279; KIAA1324; KIAA1324L; KIAA1377; KIAA1456;KIAA1462; KIAA1468; KIAA1524; KIAA1549; KIAA1551; KIAA1598; KIAA1715;KIAA1804; KIAA1841; KIAA1919; KIAA2022; KIDINS220; KIF11; KIF13A; KIF14;KIF15; KIF16B; KIF17; KIF18A; KIF1A; KIF1C; KIF20A; KIF20B; KIF21A;KIF21B; KIF22; KIF23; KIF24; KIF25; KIF26A; KIF26B; KIF2A; KIF2B; KIF2C;KIF3A; KIF3B; KIF3C; KIF4A; KIF4B; KIFSA; KIFSB; KIFSC; KIF6; KIF7;KIF9; KIFAP3; KIFC1; KIFC3; KIN; KIR2DL1; KIR2DL2; KIR2DL3; KIR2DL4;KIR2DL5A; KIR2DL5B; KIR2DS1; KIR2DS2; KIR2DS3; KIR2DS4; KIR3DL1;KIR3DL2; KIR3DL3; KIRREL2; KIRREL3; KIRREL; KISS1; KISS1R; KIT; KITLG;KLB; KLC1; KLF10; KLF11; KLF12; KLF13; KLF14; KLF15; KLF16; KLF1; KLF2;KLF3; KLF4; KLF5; KLF6; KLF7; KLF8; KLF9; KLHDC1; KLHDC2; KLHDC8A;KLHDC8B; KLHL10; KLHL12; KLHL1; KLHL20; KLHL25; KLHL26; KLHL29; KLHL2;KLHL31; KLHL35; KLHL3; KLHL40; KLHL41; KLHL42; KLHL5; KLHL6; KLHL7;KLHL9; KL; KLK10; KLK11; KLK12; KLK13; KLK14; KLK15; KLK1; KLK2; KLK3;KLK4; KLK5; KLK6; KLK7; KLK8; KLK9; KLKB1; KLLN; KLRB1; KLRC1; KLRC2;KLRC4; KLRC4-KLRK1; KLRD1; KLRG1; KLRG2; KMO; KMT2A; KMT2B; KMT2C;KMT2D; KMT2E; KNG1; KNSTRN; KNTC1; KPNA1; KPNA2; KPNA3; KPNA4; KPNA6;KPNA7; KPNB 1; KPRP; KPTN; KRAS; KRBOX4; KREMEN1; KRIT1; KRT10; KRT12;KRT13; KRT14; KRT15; KRT16; KRT17; KRT18; KRT19; KRT1; KRT20; KRT23;KRT2; KRT31; KRT32; KRT34; KRT35; KRT3; KRT4; KRTS; KRT6A; KRT6B; KRT6C;KRT71; KRT72; KRT74; KRT75; KRT76; KRT78; KRT7; KRT80; KRT81; KRT82;KRT83; KRT85; KRT86; KRT8; KRT9; KRTAP11-1; KRTAPS-1; KRTAPS-9; KSR1;KSR2; KTN1; KYNU; L1CAM; L2HGDH; L3MBTL1; L3MBTL2; L3MBTL3; L3MBTL4;LACC1; LACE1; LACRT; LACTB; LAD1; LAG3; LAIR1; LAIR2; LALBA; LAMA1;LAMA2; LAMA3; LAMA4; LAMA5; LAMB 1; LAMB 2; LAMB3; LAMB 4; LAMC 1;LAMC2; LAMC3; LAMP1; LAMP2; LAMP3; LAMTOR1; LAMTOR2; LAMTOR3; LANCL1;LANCL2; LAP3; LAPTM4B; LARGE; LARP1; LARP4; LARP6; LARP7; LARS2; LARS;LAS1L; LASP1; LAT2; LAT; LATS1; LATS2; LAX1; LAYN; LBH; LBP; LBR; LBX1;LBX2; LCA5; LCAT; LCE1C; LCE3A; LCE3B; LCE3C; LCE3D; LCE3E; LCE5A; LCK;LCLAT1; LCMT1; LCN1; LCN2; LCOR; LCP1; LCP2; LCT; LDB1; LDB2; LDB3;LDHA; LDHAL6B; LDHB; LDHC; LDHD; LDLRAD3; LDLRAD4; LDLR; LDOC1; LDOC1L;LEAP2; LECT1; LECT2; LEF1; LEFTY1; LEFTY2; LEKR1; LEMD2; LEMD3; LEO1;LEP; LEPROTL1; LETM1; LETMD1; LEUTX; LFNG; LGALS12; LGALS13; LGALS14;LGALS16; LGALS1; LGALS2; LGALS3BP; LGALS3; LGALS4; LGALS7B; LGALS8;LGALS9; LGALSL; LGI1; LGI2; LGI4; LGMN; LGR4; LGRS; LGR6; LGSN; LHB;LHCGR; LHFP; LHFPL1; LHFPL2; LHFPL3; LHFPL4; LHFPL5; LHPP; LHX1; LHX2;LHX3; LHX4; LHX5; LHX6; LHX9; LIAS; LIF; LIFR; LIG1; LIG3; LIG4; LILRA1;LILRA2; LILRA3; LILRA4; LILRA5; LILRB1; LILRB2; LILRB3; LILRB4; LILRB5;LIM2; LIMA1; LIMCH1; LIMD1; LIMD2; LIMK1; LIMK2; LIMS1; LIMS2; LIN28B;LIN52; LIN7A; LIN7B; LIN7C; LIN9; LINGO1; LINGO2; LINGO4; LINS; LIPA;LIPC; LIPE; LIPF; LIPG; LIPH; LIPI; LIPN; LIPT1; LIPT2; LITAF; LIX1;LLGL1; LLGL2; LMAN1; LMAN1L; LMAN2L; LMBR1; LMBRD1; LMBRD2; LMCD1; LMF1;LMLN; LMNA; LMNB1; LMNB2; LMNTD1; LMO1; LMO2; LMO3; LMO7; LMOD1; LMOD3;LMTK2; LMTK3; LMX1A; LMX1B; LNPEP; LNX1; LNX2; LOC100288966;LOC101060321; LOC102723475; LOC102723996; LOC102724127; LOC102724560;LOC102724770; LOC102725016; LOC102725035; LOC400499; LOC400927-CSNK1E;LOC645177; LONP1; LONRF1; LOR; LOXHD1; LOX; LOXL1; LOXL2; LOXL3; LOXL4;LPA; LPAR1; LPAR2; LPAR3; LPAR6; LPCAT1; LPCAT2; LPCAT3; LPCAT4; LPGAT1;LPIN1; LPIN2; LPL; LPO; LPP; LPPR2; LPPR4; LPXN; LRAT; LRBA; LRCH1;LRCH4; LRFN2; LRFN5; LRG1; LRGUK; LRIF1; LRIG1; LRIG3; LRIT1; LRIT3;LRMP; LRP10; LRP12; LRP1B; LRP1; LRP2BP; LRP2; LRP4; LRP5; LRP6; LRPAP1;LRPPRC; LRR1; LRRC15; LRRC16A; LRRC16B; LRRC17; LRRC18; LRRC1; LRRC20;LRRC26; LRRC30; LRRC32; LRRC37A; LRRC37B; LRRC39; LRRC49; LRRC4B;LRRC4C; LRRC4; LRRC52; LRRC59; LRRC61; LRRC63; LRRC69; LRRC6; LRRC74A;LRRC7; LRRC8A; LRRC8C; LRRCC1; LRRFIP1; LRRFIP2; LRRK1; LRRK2; LRRN1;LRRN2; LRRN3; LRRN4; LRRTM1; LRRTM2; LRRTM3; LRRTM4; LRSAM1; LRTM1;LRTOMT; LSAMP; LSM11; LSM1; LSM2; LSM3; LSM4; LSMS; LSM6; LSM7; LSP1;LSR; LSS; LST1; LTA4H; LTA; LTB4R2; LTB4R; LTB; LTBP1; LTBP2; LTBP3;LTBP4; LTBR; LTC4S; LTF; LTK; LUC7L3; LUC7L; LUM; LURAP1L; LUZP4; LUZP6;LVRN; LXN; LY6D; LY6E; LY6G5B; LY6G5C; LY6G6C; LY6G6F; LY6K; LY75-CD302;LY75; LY86; LY96; LY9; LYL1; LYN; LYNX1; LYPD1; LYPD2; LYPD3; LYPD4;LYPDS; LYPD6; LYPD8; LYPLA1; LYPLAL1; LYRM1; LYRM4; LYRM7; LYRM9; LYST;LYVE1; LYZ; LYZL1; LYZL2; LYZL6; LZTFL1; LZTR1; LZTS1; M6PR; MAATS1;MAB21L1; MAB21L2; MAB 21L3; MACC1; MACROD1; MACROD2; MAD1L1; MAD2L1BP;MAD2L1; MAD2L2; MADCAM1; MADD; MAEA; MAEL; MAF1; MAFA; MAFB; MAFF; MAFG;MAF; MAFK; MAGEA10; MAGEA11; MAGEA12; MAGEA1; MAGEA2B; MAGEA3; MAGEA4;MAGEA6; MAGEA9; MAGEB17; MAGEB1; MAGEB2; MAGEB6; MAGEC1; MAGEC2; MAGEC3;MAGED1; MAGED2; MAGED4B; MAGED4; MAGEE1; MAGEH1; MAGEL2; MAG; MAGI1;MAGI2; MAGI3; MAGT1; MAK16; MAK; MAL; MALL; MALRD1; MALT1; MAML1; MAML2;MAML3; MAMLD1; MAN1A1; MAN1B1; MAN2A1; MAN2A2; MAN2B 1; MAN2C1; MANBA;MANEA; MANF; MANSC1; MAOA; MAOB; MAP10; MAP1A; MAP1B; MAP1LC3A;MAP1LC3B2; MAP1LC3B; MAP1S; MAP2; MAP2K1; MAP2K2; MAP2K3; MAP2K4;MAP2K5; MAP2K6; MAP2K7; MAP3K10; MAP3K11; MAP3K12; MAP3K13; MAP3K14;MAP3K19; MAP3K1; MAP3K2; MAP3K3; MAP3K4; MAP3K5; MAP3K6; MAP3K7CL;MAP3K7; MAP3K8; MAP3K9; MAP4; MAP4K1; MAP4K2; MAP4K3; MAP4K4; MAP4K5;MAP6; MAP7; MAP9; MAPK10; MAPK11; MAPK12; MAPK13; MAPK14; MAPK15; MAPK1;MAPK3; MAPK6; MAPK7; MAPK8; MAPK8IP1; MAPK8IP2; MAPK8IP3; MAPK9;MAPKAP1; MAPKAPK2; MAPKAPK3; MAPKBP1; MAPRE1; MAPRE2; MAPRE3; MAPT;MARC1; MARC2; MARCH1; MARCH2; MARCH5; MARCH6; MARCH7; MARCH8; MARCKS;MARCO; MARK1; MARK2; MARK3; MARK4; MARS 2; MARS; MARVELD1; MARVELD2;MARVELD3; MAS1; MAS1L; MASP1; MAST2; MAST4; MASTL; MAT1A; MAT2A; MAT2B;MATK; MATN2; MATN3; MATR3; MAU2; MAVS; MAX; MAZ; MB21D1; MB21D2; MBD1;MBD2; MBD3; MBD3L2; MBD4; MBD5; MBD6; MB; MBIP; MBL2; MBNL1; MBNL2;MBOAT1; MBOAT2; MBOAT4; MBP; MBTD1; MBTPS1; MBTPS2; MC1R; MC2R; MC3R;MC4R; MC5R; MCAM; MCAT; MCCC1; MCCC2; MCCD1; MCC; MCEE; MCF2; MCF2L2;MCF2L; MCFD2; MCHR1; MCHR2; MCIDAS; MCM10; MCM2; MCM3AP; MCM3; MCM4;MCM5; MCM6; MCM7; MCM8; MCM9; MCMBP; MCOLN1; MCOLN3; MCPH1; MCRS1;MCTP1; MCTP2; MCTS1; MCU; MCUR1; MDC1; MDFIC; MDFI; MDGA1; MDGA2; MDH1;MDH2; MDK; MDM1; MDM2; MDM4; ME1; ME2; ME3; MEA1; MECOM; MECP2; MED12;MED12L; MED13; MED13L; MED14; MED15; MED16; MED17; MED19; MED1; MED22;MED23; MED24; MED25; MED28; MED29; MED30; MED4; MED6; MEDS; MEF2A;MEF2B; MEF2BNB-MEF2B; MEF2C; MEF2D; MEFV; MEGF10; MEGF11; MEGF8; MEGF9;MEI1; MEIS1; MEIS2; MELK; MEMO1; MEN1; MEOX1; MEOX2; MEP1A; MEPE; MERTK;MESDC1; MESDC2; MESP2; MEST; METAP1D; METAP1; METAP2; MET; METRN;METTL13; METTL16; METTL17; METTL18; METTL1; METTL21A; METTL21B;METTL21C; METTL24; METTL6; METTL7A; METTL9; MEX3B; MEX3C; MEX3D; MFAP3;MFAP4; MFAP5; MFGE8; MFHAS1; MFI2; MFN1; MFRP; MFSD11; MFSD12; MFSD1;MFSD6; MFSD7; MFSD8; MGA; MGAM; MGARP; MGAT1; MGAT2; MGAT3; MGAT4A;MGAT4B; MGAT4C; MGAT5B; MGAT5; MGEA5; MGLL; MGME1; MGMT; MGP; MGRN1;MGST1; MGST2; MGST3; MIA2; MIA3; MIA; MIB1; MIB2; MICA; MICAL2; MICALCL;MICB; MICU1; MICU3; MID1; MID2; MIEN1; MIER2; MIER3; MIF; MILR1; MINA;MINK1; MINPP1; MIOX; MIPEP; MIP; MIPOL1; MIR1-1HG; MIS18BP1; MITF;MIXL1; MKI67; MKKS; MKL1; MKL2; MKLN1; MKNK1; MKNK2; MKRN1; MKRN3; MKS1;MLANA; MLC1; MLEC; MLF1; MLF2; MLH1; MLH3; MLKL; MLLT10; MLLT1; MLLT3;MLLT4; MLLT6; MLN; MLNR; MLPH; MLST8; MLX; MLXIP; MLXIPL; MLYCD; MMAA;MMAB; MMADHC; MMD2; MMD; MME; MMEL1; MMP10; MMP11; MMP12; MMP13; MMP14;MMP15; MMP16; MMP17; MMP19; MMPI; MMP20; MMP21; MMP24; MMP25; MMP26;MMP28; MMP2; MMP3; MMPI; MMP8; MMP9; MMRN1; MMRN2; MMS19; MMS22L; MN1;MNAT1; MNDA; MNS1; MNT; MNX1; MOAP1; MOB1A; MOB1B; MOB2; MOB3B; MOB4;MOBP; MOCOS; MOCS1; MOCS2; MOGAT1; MOGAT2; MOGAT3; MOG; MOGS; MOK;MON1A; MON1B; MON2; MORC3; MORF4L1; MORN1; MORN2; MORN5; MOS; MOV10L1;MPC1; MPC2; MPDU1; MPDZ; MPEG1; MPG; MPHOSPH10; MPHOSPH6; MPHOSPH8;MPHOSPH9; MPI; MPLKIP; MPO; MPP1; MPP2; MPP3; MPP5; MPP7; MPPE1; MPPED2;MPRIP; MPST; MPV17; MPV17L2; MPZ; MPZL1; MPZL2; MPZL3; MR1; MRAP2; MRAP;MRAS; MRC1; MRC2; MRE11A; MREG; MRFAP1; MRGBP; MRGPRF; MRGPRX1; MRGPRX3;MRGPRX4; MRI1; MRM1; MROH2B; MRO; MRPL10; MRPL11; MRPL13; MRPL15;MRPL17; MRPL19; MRPL1; MRPL23; MRPL28; MRPL33; MRPL36; MRPL3; MRPL40;MRPL41; MRPL44; MRPL49; MRPL52; MRPL9; MRPS 11; MRPS 12; MRPS 16; MRPS18B; MRPS22; MRPS23; MRPS28; MRPS30; MRPS31; MRPS33; MRPS6; MRPS7;MRPS9; MRRF; MRS2; MRVI1; MS4A12; MS4A1; MS4A2; MS4A3; MS4A4A; MS4A6A;MS4A8; MSANTD3-TMEFF1; MSC; MSGN1; MSH2; MSH3; MSH5; MSH6; MSI1; MSI2;MSLN; MSMB; MSMO1; MSMP; MSN; MSR1; MSRA; MSRB2; MSRB3; MST1; MST1R;MSTN; MSTO1; MSX1; MSX2; MT1A; MT1B; MT1E; MT1F; MT1G; MT1H; MT1M; MT1X;MT2A; MT3; MT4; MTA1; MTA2; MTA3; MTAP; MTBP; MTCH1; MTCH2; MTCL1;MTCP1; MTDH; MTERF1; MTF1; MTFMT; MTFP1; MTG1; MTHFD1; MTHFD1L; MTHFD2;MTHFR; MTHFS; MTIF2; MTIF3; MTL5; MTM1; MTMR11; MTMR12; MTMR14; MTMR1;MTMR2; MTMR3; MTMR4; MTMR6; MTMR7; MTMR8; MTMR9; MTNR1A; MTNR1B; MTO1;MTPAP; MTPN; MTRF1; MTR; MTRNR2L7; MTRR; MTSS1; MTTP; MTURN; MTUS1;MTUS2; MTX1; MTX2; MUC12; MUC13; MUC15; MUC17; MUC19; MUC1; MUC20;MUC21; MUC22; MUC2; MUC3A; MUC4; MUC5AC; MUC5B; MUC6; MUC7; MUCL1; MUM1;MURC; MUS81; MUSK; MUT; MUTYH; MVB12B; MVD; MVK; MVP; MX1; MX2; MXD1;MXD3; MXD4; MXI1; MXRA5; MYADM; MYBBP1A; MYB; MYBL1; MYBL2; MYBPC1;MYBPC2; MYBPC3; MYBPH; MYCBP2; MYCBPAP; MYC; MYON; MYCT1; MYD88; MYDGF;MYEF2; MYEOV; MYF5; MYF6; MYH10; MYH11; MYH13; MYH14; MYH15; MYH1; MYH2;MYH3; MYH4; MYH6; MYH7B; MYH7; MYH8; MYH9; MYL12A; MYL12B; MYL1; MYL2;MYL3; MYL4; MYL6; MYL7; MYL9; MYLIP; MYLK2; MYLK3; MYLK; MYLPF; MYNN;MYO10; MYO15A; MYO16; MYO18B; MYO1A; MYO1B; MYO1C; MYO1D; MYO1E; MYO1F;MYO3A; MYO3B; MYO5A; MYO5B; MYO5C; MYO6; MYO7A; MYO7B; MYO9A; MYO9B;MYOCD; MYOC; MYOD1; MYOF; MYOG; MYOM1; MYOM2; MYOT; MYOZ1; MYOZ2; MYOZ3;MYPN; MYRF; MYRFL; MYRIP; MYT1; MYT1L; MYZAP; MZB1; MZF1; N4BP1;N4BP2L1; N4BP2L2; NAA10; NAA15; NAA16; NAA20; NAA25; NAA30; NAA35;NAA40; NAA50; NAA60; NAAA; NAALAD2; NAALADL1; NAALADL2; NAB1; NAB2;NABP1; NABP2; NACA; NACC1; NACC2; NADSYN1; NAE1; NAF1; NAGA; NAGK;NAGLU; NAGPA; NAGS; NAIP; NALCN; NAMPT; NANOG; NANOS1; NANOS2; NANOS3;NANS; NAP1L1; NAP1L3; NAP1L4; NAP1L5; NAPA; NAPEPLD; NAPG; NAPRT; NAPSA;NARFL; NARR; NARS; NAT10; NAT14; NAT1; NAT2; NAT6; NAT8B; NAT8; NAT8L;NAV1; NAV2; NAV3; NBAS; NBEA; NBEAL1; NBEAL2; NBN; NBPF3; NBR1; NCALD;NCAM1; NCAM2; NCAN; NCAPD2; NCAPD3; NCAPG2; NCAPG; NCBP2; NCEH1; NCF1;NCF2; NCF4; NCK1; NCK2; NCKAP1; NCKAP1L; NCKAP5; NCKIPSD; NCL; NCOA1;NCOA2; NCOA3; NCOA4; NCOA5; NCOA6; NCOA7; NCOR1; NCOR2; NCR1; NCR2;NCR3; NCR3LG1; NCS1; NCSTN; NDC80; NDE1; NDEL1; NDFIP1; NDFIP2; NDNF;NDN; NDP; NDRG1; NDRG2; NDRG3; NDRG4; NDST1; NDST2; NDST3; NDST4;NDUFA10; NDUFA11; NDUFA12; NDUFA13; NDUFA1; NDUFA2; NDUFA5; NDUFA6;NDUFA9; NDUFAB1; NDUFAF1; NDUFAF2; NDUFAF3; NDUFAF4; NDUFAF5; NDUFAF6;NDUFB 10; NDUFB11; NDUFB2; NDUFB3; NDUFB4; NDUFB5; NDUFB6; NDUFB8;NDUFB9; NDUFC2; NDUFS1; NDUFS2; NDUFS3; NDUFS4; NDUFS6; NDUFS7; NDUFS8;NDUFV1; NDUFV2; NDUFV3; NEB; NEBL; NECAB1; NECAB3; NECAP1; NEDD1; NEDD4;NEDD4L; NEDD8; NEDD9; NEFH; NEFM; NEIL1; NEIL2; NEIL3; NEK10; NEK11;NEK1; NEK2; NEK3; NEK4; NEK6; NEK7; NEK8; NEK9; NELFA; NELFB; NELFCD;NELFE; NELL1; NELL2; NEMF; NEO1; NES; NET1; NETO1; NETO2; NEU1; NEU3;NEURL1; NEURL2; NEUROD1; NEUROD2; NEUROD4; NEUROD6; NEUROG1; NEUROG2;NEUROG3; NF1; NF2; NFAM1; NFASC; NFAT5; NFATC1; NFATC2; NFATC3; NFATC4;NFE2; NFE2L1; NFE2L2; NFE2L3; NFIA; NFIB; NFIC; NFIL3; NFIX; NFKB1;NFKB2; NFKBIA; NFKBIB; NFKBIE; NFKBIL1; NFKBIZ; NFRKB; NFS1; NFU1; NFYA;NFYB; NFYC; NGB; NGDN; NGEF; NGF; NGFRAP1; NGFR; NGLY1; NHEJ1; NHLH1;NHLRC1; NHLRC3; NHP2; NHP2L1; NHS; NHSL1; NICN1; NID1; NID2; NIF3L1;NIM1K; NIN; NINJ1; NINJ2; NINL; NIPA1; NIPA2; NIPAL3; NIPAL4; NIPBL;NIPSNAP1; NIPSNAP3B; NISCH; NIT1; NIT2; NKAIN2; NKAIN3; NKAP; NKD1;NKD2; NKG7; NKIRAS1; NKIRAS2; NKRF; NKTR; NKX1-1; NKX1-2; NKX2-1;NKX2-2; NKX2-3; NKX2-5; NKX2-6; NKX2-8; NKX3-1; NKX6-1; NKX6-2; NLE1;NLGN1; NLGN2; NLGN3; NLGN4X; NLGN4Y; NLK; NLN; NLRC3; NLRC4; NLRC5;NLRP10; NLRP11; NLRP12; NLRP13; NLRP14; NLRP1; NLRP2; NLRP3; NLRP4;NLRP5; NLRP6; NLRP7; NLRP8; NLRP9; NMB; NMBR; NME1; NME1-NME2; NME2;NME3; NME4; NME5; NME6; NME7; NME8; NME9; NMI; NMNAT1; NMNAT2; NMNAT3;NMS; NMT1; NMT2; NMU; NMUR1; NMUR2; NNAT; NNMT; NNT; NOA1; NOB1; NOBOX;NOC3L; NOD1; NOD2; NODAL; NOG; NOL11; NOL3; NOL4; NOL6; NOL8; NOLC1;NOM1; NOMO1; NONO; NOP10; NOP14; NOP16; NOP2; NOP56; NOP9; NOS1AP; NOS1;NOS2; NOS3; NOSIP; NOSTRIN; NOTCH1; NOTCH2; NOTCH3; NOTCH4; NOTUM;NOVA1; NOVA2; NOV; NOX1; NOX3; NOX4; NOX5; NOXA1; NOXO1; NPAP1; NPAS2;NPAS3; NPAS4; NPAT; NPB; NPBWR1; NPC1; NPC1L1; NPC2; NPDC1; NPEPL1;NPEPPS; NPFF; NPFFR2; NPHP1; NPHP3; NPHP4; NPHS1; NPHS2; NPL; NPLOC4;NPM1; NPM2; NPNT; NPPC; NPR1; NPR2; NPR3; NPRL2; NPRL3; NPS; NPSR1;NPTN; NPTX1; NPTX2; NPTXR; NPVF; NPW; NPY1R; NPY2R; NPY5R; NPY; NQO1;NQO2; NROB1; NR1D1; NR1D2; NR1H2; NR1H3; NR1H4; NR1I2; NR1I3; NR2C1;NR2C2; NR2E1; NR2E3; NR2F1; NR2F2; NR2F6; NR3C1; NR3C2; NR4A1; NR4A2;NR4A3; NR5A1; NR5A2; NR6A1; NRAP; NRARP; NRBP1; NRBP2; NRCAM; NRD1;NRDE2; NREP; NRF1; NRG1; NRG2; NRG3; NRG4; NRGN; NRIP1; NRIP2; NRK; NRL;NRM; NRN1; NRP1; NRP2; NRSN1; NRSN2; NRTN; NRXN1; NRXN2; NRXN3; NSA2;NSD1; NSDHL; NSF; NSFL1C; NSG1; NSMAF; NSMCE2; NSMF; NSRP1; NSUN2;NSUN3; NSUN5; NSUN7; NT5C1B; NT5C1B-RDH14; NT5C2; NT5C3A; NT5C; NT5DC1;NT5DC3; NT5E; NT5M; NTAN1; NTF3; NTF4; NTHL1; NTM; NTN1; NTN4; NTNG1;NTNG2; NTPCR; NTRK1; NTRK2; NTRK3; NTS; NTSR1; NTSR2; NUAK1; NUAK2;NUB1; NUBP1; NUBP2; NUBPL; NUCB1; NUCB2; NUCKS1; NUDCD1; NUDCD3; NUDC;NUDT10; NUDT11; NUDT15; NUDT19; NUDT1; NUDT21; NUDT2; NUDT3; NUDT6;NUDT7; NUF2; NUFIP1; NUFIP2; NUGGC; NUMA1; NUMB; NUMBL; NUP153; NUP155;NUP205; NUP210; NUP214; NUP35; NUP37; NUP43; NUP50; NUP62; NUP85; NUP88;NUP93; NUP98; NUPL2; NUPR1; NUS1; NUSAP1; NUTF2; NUTM1; NUTM2A; NUTM2B;NVL; NWD1; NXF1; NXF2B; NXF3; NXF5; NXN; NXNL1; NXNL2; NXPE1; NXPE2;NXPE4; NXPH1; NXPH2; NXT1; NXT2; NYAP2; NYX; OARD1; OAS1; OAS2; OAS3;OASL; OAT; OAZ1; OAZ2; OBFC1; OBP2A; OBSCN; OBSL1; OC90; OCA2; OCIAD1;OCIAD2; OCLM; OCLN; OCM2; OCM; OCRL; ODAM; ODC1; ODF1; ODF3B; ODF4;OFCC1; OFD1; OGDH; OGDHL; OGFOD1; OGFR; OGG1; OGN; OGT; OIP5; OIT3;OLA1; OLFM1; OLFM2; OLFM4; OLFML2B; OLIG1; OLIG2; OLIG3; OLR1; OMD; OMG;OMP; ONECUT1; ONECUT2; OPA1; OPA3; OPCML; OPHN1; OPN1LW; OPN1MW2;OPN1SW; OPN3; OPN4; OPN5; OPRK1; OPRL1; OPRM1; OPTC; OPTN; OR10A2;OR10A4; OR10C1; OR10J1; OR10J3; OR10J5; OR10K1; OR10K2; OR10R2; OR10T2;OR10X1; OR10Z1; OR11A1; OR12D2; OR12D3; OR13C3; OR13C4; OR13F1; OR13G1;OR13J1; OR14J1; OR1A1; OR1C1; OR1D2; OR1E1; OR1E2; OR1J2; OR1K1; OR1L8;OR1M1; OR1N1; OR1N2; OR2A25; OR2AG1; OR2AK2; OR2AT4; OR2B2; OR2B3;OR2B6; OR2C1; OR2F2; OR2G2; OR2G3; OR2H2; OR2J2; OR2J3; OR2L2; OR2M3;OR2M4; OR2M7; OR2S2; OR2T10; OR2T12; OR2T1; OR2T2; OR2T33; OR2T4; OR2T5;OR2W1; OR2Y1; OR2Z1; OR3A1; OR4A15; OR4C12; OR4C13; OR4C6; OR4D10;OR4K13; OR4P4; OR4S2; OR51A2; OR51A7; OR51E1; OR51E2; OR51F2; OR51V1;OR52B2; OR52B4; OR52D1; OR52E6; OR52I1; OR52I2; OR52K1; OR52K2; OR52M1;OR5D18; OR5H2; OR5H6; OR5K1; OR5K2; OR5V1; OR6B1; OR6B2; OR6C1; OR6F1;OR6K2; OR6K3; OR6K6; OR6N1; OR6N2; OR6X1; OR6Y1; OR7C1; OR7D2; OR7E24;OR8S1; OR9K2; OR9Q2; ORAI1; ORAI3; ORAOV1; ORC2; ORC3; ORC4; ORC5; ORC6;ORM1; ORM2; ORMDL3; OS9; OSBP2; OSBP; OSBPL10; OSBPL11; OSBPL1A; OSBPL2;OSBPL3; OSBPL5; OSBPL6; OSBPL8; OSBPL9; OSCAR; OSER1; OSGEP; OSGIN1;OSM; OSMR; OSR1; OSR2; OSTF1; OSTM1; OTC; OTOA; OTOF; OTOG; OTOGL;OTOL1; OTOP1; OTOR; OTP; OTUB1; OTUD1; OTUD4; OTUD7A; OTUD7B; OTULIN;OTX1; OTX2; OVCA2; OVOL1; OVOL2; OXA1L; OXCT1; OXER1; OXGR1; OXR1;OXSR1; OXT; OXTR; P2RX1; P2RX2; P2RX3; P2RX4; P2RX5; P2RX6; P2RX7;P2RY11; P2RY12; P2RY13; P2RY14; P2RY1; P2RY2; P2RY4; P2RY6; P2RY8; P3H2;P3H3; P3H4; P4HA1; P4HA2; P4HB; P4HTM; PA2G4; PABPC1; PABPC3; PABPC4L;PABPN1; PACRG; PACS1; PACS2; PACSIN1; PACSIN2; PADI4; PAEP; PAF1;PAFAH1B1; PAFAH1B2; PAFAH2; PAG1; PAGE1; PAGE4; PAGE5; PAGR1; PAH;PAICS; PAIP1; PAIP2; PAK1; PAK1IP1; PAK2; PAK3; PAK4; PAK6; PAK7; PALB2;PALD1; PALLD; PALM2-AKAP2; PAM16; PAM; PAMR1; PAN2; PAN3; PANK1; PANK2;PANX1; PANX2; PAOX; PAPD7; PAPL; PAPOLA; PAPOLG; PAPPA2; PAPPA; PAPSS1;PAPSS2; PAQR3; PAQR5; PAQR7; PARD3B; PARD3; PARD6A; PARD6B; PARG; PARK2;PARL; PARM1; PARN; PARP12; PARP14; PARP15; PARP1; PARP2; PARP3; PARP4;PARP6; PARP9; PARPBP; PARS2; PARVA; PARVB; PARVG; PASD1; PASK; PATE1;PATZ1; PAWR; PAX1; PAX2; PAX3; PAX4; PAX5; PAX6; PAX8; PAX9; PAXIP1;PBK; PBLD; PBOV1; PBRM1; PBX1; PBX2; PBX3; PBX4; PCBD1; PCBD2; PCBP1;PCBP2; PCBP3; PCBP4; PCCA; PCCB; PCDH10; PCDH11X; PCDH11Y; PCDH15;PCDH17; PCDH18; PCDH19; PCDH1; PCDH20; PCDH7; PCDH8; PCDH9; PCDHA1;PCDHA4; PCDHA6; PCDHB1; PCDHB2; PCDHB3; PCDHB8; PCDHGA11; PCDHGA3;PCDHGB4; PCDHGB6; PCDHGC3; PCED1B; PCF11; PCGF1; PCGF2; PCGF3; PCGF6;PC; PCID2; PCK1; PCK2; PCLO; PCM1; PCMT1; PCMTD1; PCNA; PCNT; PCNXL2;PCNXL4; PCOLCE2; PCOLCE; PCP2; PCP4; PCSK1; PCSK1N; PCSK2; PCSK4; PCSK5;PCSK6; PCSK7; PCTP; PCYT1A; PCYT1B; PDAP1; PDCD10; PDCD1; PDCD1LG2;PDCD2; PDCD4; PDCD5; PDCD6; PDCD6IP; PDCD7; PDC; PDCL2; PDCL3; PDE10A;PDE11A; PDE12; PDE1A; PDE1B; PDE1C; PDE2A; PDE3A; PDE3B; PDE4A; PDE4D;PDE5A; PDE6A; PDE6B; PDE6C; PDE6D; PDE6G; PDE6H; PDE7A; PDE7B; PDE8A;PDE8B; PDE9A; PDF; PDGFA; PDGFB; PDGFC; PDGFD; PDGFRA; PDGFRB; PDGFRL;PDHA1; PDHB; PDHX; PDIA2; PDIA3; PDIA4; PDIA5; PDIA6; PDK1; PDK2; PDK3;PDK4; PDLIM1; PDLIM2; PDLIM3; PDLIM4; PDLIM5; PDLIM7; PDP1; PDP2; PDPK1;PDPR; PDRG1; PDS5A; PDS5B; PDSS1; PDSS2; PDX1; PDXDC1; PDXK; PDXP; PDYN;PDZD2; PDZD4; PDZD7; PDZD8; PDZK1; PDZRN3; PDZRN4; PEA15; PEAK1; PEAR1;PEBP1; PEBP4; PECAM1; PECR; PEG10; PEG3; PELI1; PELI2; PELP1; PEMT;PENK; PEPD; PER1; PER2; PER3; PERM1; PERP; PES1; PET100; PET117; PEX11A;PEX12; PEX13; PEX14; PEX16; PEX19; PEX1; PEX26; PEX2; PEX3; PEX5; PEX5L;PEX6; PEX7; PF4; PF4V1; PFDN4; PFDN5; PFDN6; PFKFB1; PFKFB2; PFKFB3;PFKFB4; PFKL; PFKM; PFKP; PFN1; PFN2; PGA3; PGA4; PGA5; PGAM1; PGAM2;PGAM4; PGAP1; PGAP2; PGAP3; PGBD1; PGBD5; PGC; PGD; PGF; PGGT1B; PGK1;PGK2; PGLS; PGLYRP1; PGLYRP2; PGLYRP3; PGLYRP4; PGM3; PGPEP1; PGP; PGR;PGRMC1; PGRMC2; PHACTR1; PHACTR2; PHACTR3; PHB2; PHB; PHC1; PHC2; PHC3;PHEX; PHF10; PHF11; PHF12; PHF19; PHF1; PHF20; PHF21A; PHF23; PHF2;PHF3; PHF5A; PHF6; PHF8; PHGDH; PHIP; PHKA1; PHKA2; PHKB; PHKG1; PHKG2;PHLDA1; PHLDA2; PHLDA3; PHLDB1; PHLPP1; PHLPP2; PHOX2A; PHOX2B; PHPT1;PHRF1; PHTF1; PHTF2; PHYH; PHYHIP; PHYKPL; PI15; PI16; PI3; PI4K2A;PI4K2B; PI4KA; PI4KB; PIAS1; PIAS2; PIAS4; PIBF1; PICALM; PICK1; PID1;PIDD1; PIEZO1; PIEZO2; PIF1; PIFO; PIGA; PIGF; PIGG; PIGL; PIGM; PIGN;PIGO; PIGP; PIGQ; PIGR; PIGT; PIGU; PIGW; PIGY; PIH1D1; PIK3AP1;PIK3C2A; PIK3C2B; PIK3C2G; PIK3C3; PIK3CA; PIK3CB; PIK3CD; PIK3CG;PIK3IP1; PIK3R1; PIK3R2; PIK3R3; PIK3R4; PIK3R5; PIKFYVE; PILRA; PIM1;PIM2; PIM3; PIN1; PIN4; PINX1; PIP4K2A; PIP4K2B; PIP4K2C; PIP5K1A;PIP5K1B; PIP5K1C; PIP5KL1; PIP; PIPDX; PIR; PISD; PITPNA; PITPNM1;PITPNM3; PITRM1; PITX1; PITX2; PITX3; PIWIL1; PIWIL2; PIWIL3; PIWIL4;PJA1; PJA2; PKD1; PKD1L1; PKD1L2; PKD1L3; PKD2; PKD2L1; PKDCC; PKDREJ;PKHD1; PKIA; PKIB; PKLR; PKM; PKMYT1; PKN1; PKN2; PKN3; PKNOX1; PKNOX2;PKP1; PKP2; PKP3; PKP4; PLA1A; PLA2G10; PLA2G12A; PLA2G12B; PLA2G15;PLA2G16; PLA2G1B; PLA2G3; PLA2G4A; PLA2G4B; PLA2G4C; PLA2G4D; PLA2G5;PLA2G6; PLA2G7; PLA2R1; PLAA; PLAC1; PLAC8; PLAG1; PLAGL1; PLAGL2; PLAT;PLAU; PLAUR; PLB1; PLBD1; PLCB1; PLCB2; PLCB3; PLCB4; PLCD1; PLCD3;PLCD4; PLCE1; PLCG1; PLCG2; PLCH1; PLCL1; PLCL2; PLCXD2; PLCXD3; PLCZ1;PLD1; PLD2; PLD3; PLD4; PLD5; PLEC; PLEK2; PLEKHA1; PLEKHA2; PLEKHA5;PLEKHA6; PLEKHA7; PLEKHB1; PLEKHD1; PLEKHF1; PLEKHF2; PLEKHG1; PLEKHG2;PLEKHG3; PLEKHG4; PLEKHG6; PLEKHH2; PLEKHM1; PLEKHO1; PLEKHO2; PLEK;PLG; PLGLB2; PLIN1; PLIN2; PLIN3; PLIN4; PLIN5; PLK1; PLK2; PLK4; PLK5;PLLP; PLN; PLOD2; PLP1; PLP2; PLRG1; PLS1; PLS3; PLSCR1; PLSCR3; PLSCR4;PLSCR5; PLTP; PLVAP; PLXDC1; PLXDC2; PLXNA1; PLXNA2; PLXNA3; PLXNA4;PLXNB1; PLXNB3; PLXNC1; PLXND1; PM20D1; PMAIP1; PMCH; PMEL; PMEPA1;PMF1-BGLAP; PMF1; PML; PMM1; PMM2; PMP22; PMPCA; PMPCB; PMS1; PMS2;PMVK; PNCK; PNKD; PNKP; PNLDC1; PNLIP; PNLIPRP2; PNMA1; PNMA2; PNMT;PNN; PNO1; PNOC; PNP; PNPLA1; PNPLA2; PNPLA3; PNPLA4; PNPLA5; PNPLA6;PNPLA8; PNPO; PNPT1; PNRC1; POC1A; POC1B; POC5; PODXL; POF1B; POFUT1;POFUT2; POGK; POGLUT1; POLA1; POLA2; POLB; POLD1; POLD2; POLD3; POLD4;POLDIP3; POLE2; POLE3; POLE4; POLE; POLG2; POLG; POLH; POLI; POLK; POLL;POLM; POLN; POLQ; POLR1A; POLR1B; POLR1C; POLR1D; POLR2A; POLR2B;POLR2C; POLR2D; POLR2E; POLR2F; POLR2G; POLR2H; POLR2J; POLR2K; POLR2M;POLR3A; POLR3B; POLR3E; POLR3K; POLRMT; POM121; POMC; POMGNT1; POMGNT2;POMK; POMP; POMT1; POMT2; POMZP3; PON1; PON2; PON3; POP1; POP4; POPDC3;PORCN; POR; POSTN; POT1; POTED; POTEF; POTEG; POTEH; POTEM; POU1F1;POU2AF1; POU2F1; POU2F2; POU2F3; POU3F2; POU3F3; POU3F4; POU4F1; POU4F2;POU4F3; POU5F1B; POU5F1; POU6F1; POU6F2; PPA1; PPA2; PPAP2A; PPAP2C;PPAPDC1B; PPAPDC2; PPAPDC3; PPARA; PPARD; PPARGC1A; PPARGC 1B; PPARG;PPAT; PPBP; PPCDC; PPEF1; PPEF2; PPFIA 1; PPFIA2; PPFIA4; PPFIBP1;PPFIBP2; PPIA; PPIB; PPIC; PPID; PPIF; PPIG; PPIL1; PPIL2; PPIL3;PPIP5K1; PPL; PPM1A; PPM1B; PPM1D; PPM1E; PPM1F; PPM1G; PPM1H; PPM1K;PPM1L; PPM1M; PPME1; PPDX; PPP1CA; PPP1CC; PPP1R10; PPP1R11; PPP1R12A;PPP1R12B; PPP1R12C; PPP1R13B; PPP1R13L; PPP1R14A; PPP1R14B; PPP1R14C;PPP1R15A; PPP1R15B; PPP1R17; PPP1R18; PPP1R1A; PPP1R1B; PPP1R2; PPP1R3A;PPP1R3B; PPP1R3C; PPP1R42; PPP1R7; PPP1R9A; PPP2CA; PPP2CB; PPP2R1A;PPP2R1B; PPP2R2A; PPP2R2B; PPP2R2C; PPP2R3A; PPP2R3B; PPP2R4; PPP2R5A;PPP2R5B; PPP2R5C; PPP2R5D; PPP2R5E; PPP3CA; PPP3CB; PPP3CC; PPP3R1;PPP3R2; PPP4C; PPP4R1; PPP5C; PPP6C; PPP6R2; PPP6R3; PPRC1; PPT2; PPY;PQBP1; PQLC3; PRAC1; PRAC2; PRADC1; PRAF2; PRAM1; PRAME; PRAP1; PRB1;PRB2; PRB3; PRB4; PRC1; PRCC; PRCD; PRCP; PRDM10; PRDM11; PRDM13;PRDM14; PRDM1; PRDM4; PRDM5; PRDM6; PRDM7; PRDM8; PRDM9; PRDX2; PRDX3;PRDX4; PRDX5; PRDX6; PREB; PRELP; PREP; PREPL; PREX1; PREX2; PRF1; PRG2;PRG4; PRH1; PRH2; PRICKLE1; PRICKLE2; PRICKLE4; PRIM1; PRIMA1; PRIMPOL;PRKAA1; PRKAB1; PRKACA; PRKACB; PRKACG; PRKAG1; PRKAG2; PRKAG3; PRKAR1A;PRKAR1B; PRKAR2A; PRKAR2B; PRKCA; PRKCB; PRKCDBP; PRKCD; PRKCE; PRKCG;PRKCH; PRKCI; PRKCQ; PRKCSH; PRKCZ; PRKD1; PRKD3; PRKDC; PRKG1; PRKG2;PRKRA; PRKRIR; PRKX; PRLH; PRL; PRLHR; PRLR; PRM1; PRM2; PRM3; PRMT1;PRMT2; PRMT3; PRMT5; PRMT8; PRND; PRNP; PROC; PROCR; PRODH; PROK2;PROKR1; PROKR2; PROL1; PROM1; PROM2; PROP1; PROS1; PROSER1; PROX1; PROZ;PRPF19; PRPF31; PRPF38B; PRPF3; PRPF40A; PRPF4B; PRPF4; PRPF6; PRPF8;PRPH2; PRPH; PRPS 1; PRPS1L1; PRPS2; PRPSAP1; PRPSAP2; PRR11; PRR13;PRR15; PRR16; PRR34; PRR3; PRR5; PRR9; PRRC1; PRRC2A; PRRC2C; PRRG4;PRRT1; PRRT2; PRRX1; PRRX2; PRS S 12; PRS S 16; PRSS1; PRSS21; PRSS22;PRSS23; PRSS27; PRSS2; PRSS33; PRSS35; PRSS3; PRSS50; PRSS53; PRSS55;PRSS57; PRSS58; PRSS8; PRTFDC1; PRTG; PRTN3; PRUNE2; PRUNE; PRX; PRY;PSAP; PSAT1; PSCA; PSD3; PSD4; PSD; PSEN1; PSEN2; PSENEN; PSG1; PSG2;PSG5; PSG6; PSG8; PSG9; PSIP1; PSKH1; PSMA1; PSMA2; PSMA3; PSMA4; PSMA6;PSMA7; PSMB10; PSMB1; PSMB4; PSMB5; PSMB6; PSMB7; PSMB8; PSMB9; PSMC1;PSMC2; PSMC3; PSMC3IP; PSMC4; PSMC5; PSMC6; PSMD10; PSMD12; PSMD13;PSMD14; PSMD1; PSMD2; PSMD3; PSMD4; PSMD6; PSMD7; PSMD8; PSMD9; PSME1;PSME2; PSME3; PSME4; PSMF1; PSMG1; PSMG2; PSMG3; PSORS1C1; PSORS1C2;PSPC1; PSPH; PSPN; PSTPIP1; PSTPIP2; PTBP1; PTBP2; PTCD1; PTCH1; PTCHD1;PTCHD4; PTCRA; PTDSS1; PTEN; PTER; PTF1A; PTGDR2; PTGDR; PTGDS; PTGER1;PTGER2; PTGER3; PTGER4; PTGES2; PTGES3; PTGES; PTGIR; PTGIS; PTGR1;PTGS1; PTGS2; PTH1R; PTH2; PTH2R; PTH; PTHLH; PTK2B; PTK2; PTK6; PTK7;PTMA; PTMS; PTN; PTOV1; PTP4A1; PTP4A3; PTPMT1; PTPN11; PTPN12; PTPN13;PTPN14; PTPN18; PTPN1; PTPN21; PTPN22; PTPN23; PTPN2; PTPN3; PTPN4;PTPN5; PTPN6; PTPN7; PTPN9; PTPRA; PTPRB; PTPRCAP; PTPRD; PTPRE; PTPRG;PTPRH; PTPRJ; PTPRK; PTPRM; PTPRN2; PTPRN; PTPRO; PTPRQ; PTPRR; PTPRS;PTPRT; PTPRZ1; PTRF; PTRH1; PTRH2; PTRHD1; PTS; PTTG1; PTTG1IP; PTTG2;PTX3; PUF60; PUM2; PURA; PURB; PUS10; PUS1; PVALB; PVR; PVRL1; PVRL2;PVRL3; PVRL4; PWP2; PWWP2B; PXDN; PXDNL; PXK; PXMP2; PXN; PXT1; PYCARD;PYCR1; PYDC1; PYDC2; PYGB; PYGL; PYGM; PYGO1; PYGO2; PYHIN1; PYROXD1;PYY; PZP; QARS; QDPR; QKI; QPCT; QPCTL; QPRT; QRFP; QRFPR; QRSL1; QSOX1;QSOX2; QTRT1; R3HCC1; R3HCC1L; R3HDM1; R3HDML; RAB11A; RAB11B;RAB11FIP1; RAB11FIP2; RAB11FIP3; RAB11FIP4; RAB11FIP5; RAB12; RAB14;RAB15; RAB18; RAB1A; RAB1B; RAB20; RAB21; RAB22A; RAB23; RAB24; RAB25;RAB27A; RAB27B; RAB28; RAB29; RAB2A; RAB31; RAB32; RAB33B; RAB34; RAB35;RAB36; RAB37; RAB38; RAB39A; RAB39B; RAB3A; RAB3D; RAB3GAP1; RAB3GAP2;RAB3IL1; RAB3IP; RAB40AL; RAB40B; RAB40C; RAB4A; RAB4B; RAB5A; RAB5B;RAB5C; RAB6A; RAB6B; RAB6C; RAB7A; RAB8A; RAB8B; RAB9A; RABAC1; RABEP1;RABEP2; RABEPK; RABGAP1L; RABGEF1; RABIF; RABL6; RAC1; RAC2; RAC3;RACGAP1; RAD17; RAD18; RAD1; RAD21; RAD21L1; RAD23A; RAD23B; RAD50;RAD51AP1; RAD51B; RAD51C; RAD51D; RAD51; RAD52; RAD54B; RAD9A; RAD9B;RAE1; RAET1E; RAET1L; RAF1; RAG1; RAG2; RAI14; RAI1; RAI2; RALA; RALB;RALBP1; RALGAPA1; RALGAPA2; RALGAPB; RALGDS; RALGPS1; RALY; RALYL;RAMP1; RAMP2; RAMP3; RANBP10; RANBP17; RANBP1; RANBP2; RANBP3; RANBP3L;RANBP6; RANBP9; RANGAP1; RANGRF; RAN; RAP1B; RAP1GAP2; RAP1GDS1; RAP2A;RAP2B; RAPGEF1; RAPGEF2; RAPGEF3; RAPGEF4; RAPGEF5; RAPH1; RAPSN; RARA;RARB; RARG; RARRES1; RARRES2; RARRES3; RARS2; RARS; RASA1; RASA2;RASAL1; RASAL2; RASD1; RASD2; RASEF; RASGEF1A; RASGEF1C; RASGRF1;RASGRF2; RASGRP1; RASGRP2; RASGRP3; RASGRP4; RASIP1; RASL10A; RASL10B;RASL11A; RASL11B; RASL12; RASSF1; RASSF2; RASSF3; RASSF4; RASSF5;RASSF6; RASSF7; RASSF8; RAX2; RAX; RB1CC1; RB1; RBAK; RBBP5; RBBP6;RBBP7; RBBP8; RBBP9; RBCK1; RBFOX1; RBFOX2; RBFOX3; RBL1; RBL2; RBM10;RBM12; RBM14; RBM14-RBM4; RBM15; RBM17; RBM20; RBM25; RBM26; RBM27;RBM28; RBM38; RBM39; RBM3; RBM45; RBM46; RBM47; RBM4; RBM5; RBM6; RBM7;RBMS1; RBMS2; RBMS3; RBMX2; RBMX; RBMXL2; RBMY1A1; RBP1; RBP2; RBP3;RBP4; RBPJ; RBPMS2; RBSN; RBX1; RC3H1; RCAN1; RCAN2; RCBTB1; RCBTB2;RCHY1; RCL1; RCN1; RCN2; RCOR1; RCSD1; RCVRN; RD3; RDH10; RDH11; RDH12;RDH14; RDH16; RDH5; RDH8; RDM1; RDX; REC8; RECK; RECQL5; RECQL; REEP1;REEP2; REEP3; REEP5; REEP6; REG1A; REG1B; REG3A; RELA; RELB; REL; RELN;REM1; RENBP; REN; REPS1; REPS2; RERG; RERGL; REST; RET; RETN; RETNLB;RETSAT; REV1; REV3L; REXO1; REXO2; REXO4; RFC1; RFC2; RFC3; RFC4; RFC5;RFFL; RFK; RFPL1; RFT1; RFTN1; RFTN2; RFWD2; RFWD3; RFX1; RFX2; RFX3;RFX4; RFX5; RFX6; RFX8; RFXANK; RFXAP; RGCC; RGL1; RGL2; RGL4; RGMA;RGMB; RGN; RGPD2; RGR; RGS10; RGS11; RGS12; RGS13; RGS14; RGS16; RGS17;RGS18; RGS19; RGS1; RGS20; RGS21; RGS22; RGS2; RGS3; RGS4; RGS5; RGS6;RGS7BP; RGS7; RGS8; RGS9BP; RGS9; RGSL1; RHAG; RHBDD2; RHBDD3; RHBDF1;RHBDF2; RHBDL1; RHBDL2; RHCE; RHCG; RHEB; RHEBL1; RHNO1; RHOB; RHOBTB1;RHOBTB2; RHOBTB3; RHOD; RHOF; RHOG; RHOH; RHO; RHOJ; RHOQ; RHOT1; RHOU;RHOV; RHOXF1; RHOXF2; RHPN1; RHPN2; RIBC2; RIC1; RIC3; RICTOR; RIF1;RILP; RILPL1; RIMBP2; RIMBP3C; RIMS1; RIMS2; RIMS4; RIN1; RIN2; RIN3;RING1; RINT1; RIOK1; RIOK2; RIOK3; RIPK1; RIPK2; RIPK3; RIPK4; RIPPLY2;RIT1; RIT2; RITA1; RLBP1; RLF; RLIM; RLN1; RLN2; RLN3; RMDN1; RMDN2;RMDN3; RMI1; RMI2; RMND1; RNASE11; RNASE12; RNASE13; RNASE1; RNASE2;RNASE3; RNASE4; RNASE6; RNASE7; RNASE8; RNASE9; RNASEH1; RNASEH2A;RNASEH2B; RNASEH2C; RNASEK; RNASEL; RNASET2; RND1; RND3; RNF103-CHMP3;RNF103; RNF111; RNF112; RNF114; RNF123; RNF125; RNF128; RNF130; RNF135;RNF138; RNF139; RNF144A; RNF144B; RNF146; RNF149; RNF14; RNF150; RNF152;RNF157; RNF167; RNF168; RNF170; RNF180; RNF182; RNF19A; RNF207; RNF20;RNF213; RNF214; RNF216; RNF24; RNF2; RNF31; RNF34; RNF39; RNF40; RNF41;RNF43; RNF44; RNF4; RNF5; RNF6; RNF7; RNF8; RNGTT; RNH1; RNLS; RNMT;RNPEP; RNPEPL1; RNPS1; ROBO1; ROBO2; ROBO3; ROBO4; ROCK1; ROCK2; ROGDI;ROM1; ROPN1B; ROPN1; ROPN1L; ROR1; ROR2; RORA; RORB; RORC; ROS1; RP1;RP1L1; RP2; RP9; RPA1; RPA2; RPA3; RPA4; RPAIN; RPAP1; RPE; RPGR;RPGRIP1; RPGRIP1L; RPH3A; RPH3AL; RPIA; RPL10A; RPL10; RPL10L; RPL12;RPL13; RPL14; RPL15; RPL17-C18orf32; RPL17; RPL18; RPL19; RPL21; RPL23A;RPL23; RPL24; RPL27A; RPL29; RPL30; RPL31; RPL34; RPL35; RPL36A;RPL36AL; RPL37A; RPL38; RPL39; RPL39L; RPL3; RPL41; RPL4; RPL6; RPL7A;RPL7; RPLP0; RPLP1; RPN1; RPN2; RPP14; RPP21; RPP25; RPP38; RPP40;RPRD1A; RPRD1B; RPRD2; RPRM; RPS10; RPS14; RPS15A; RPS16; RPS18;RPS19BP1; RPS20; RPS24; RPS27A; RPS27; RPS27L; RPS29; RPS2; RPS3A; RPS3;RPS4X; RPS4Y1; RPS6KA2; RPS6KA3; RPS6KA4; RPS6KA5; RPS6KA6; RPS6KB1;RPS6KB2; RPS9; RPSA; RPTOR; RQCD1; RRAD; RRAGA; RRAS2; RRAS; RRBP1;RREB1; RRH; RRM1; RRM2B; RRM2; RRN3; RRNAD1; RRP1B; RRP1; RRP9; RRS1;RS1; RSAD2; RSF1; RSL1D1; RSL24D1; RSPH1; RSPH4A; RSPH9; RSPO2; RSPO3;RSPO4; RSRC1; RSRC2; RSRP1; RSU1; RTCB; RTEL1; RTKN2; RTKN; RTL1; RTN1;RTN2; RTN3; RTN4; RTN4IP1; RTN4R; RTP3; RTP4; RTTN; RUFY1; RUFY3;RUNDC3B; RUNX1; RUNX1T1; RUNX2; RUNX3; RUVBL1; RUVBL2; RXFP1; RXFP2;RXFP3; RXRA; RXRB; RXRG; RYBP; RYK; RYR1; RYR2; RYR3; S100A10; S100A11;S100A12; S100A13; S100A14; S100A16; S100A1; S100A2; S100A3; S100A4;S100A5; S100A6; S100A7A; S100A7; S100A8; S100A9; S100B; S100P; S100Z;S1PR2; S1PR3; S1PR4; S1PR5; SAA1; SAA2; SAA4; SAAL1; SAC3D1; SACM1L;SACS; SAE1; SAFB2; SAFB; SAGE1; SAG; SALL1; SALL2; SALL3; SALL4; SAMD14;SAMD1; SAMD4A; SAMD5; SAMD9; SAMD9L; SAMHD1; SAMM50; SAMSN1; SAP3OBP;SAP30L; SAPCD1; SAPCD2; SAR1A; SAR1B; SARDH; SARM1; SARNP; SARS2; SART1;SART3; SASH1; SASH3; SAT1; SAT2; SATB1; SATB2; SATL1; SAV1; SBDS; SBF1;SBF2; SBNO1; SBNO2; SBSN; SC5D; SCAF11; SCAF1; SCAF4; SCAF8; SCAI;SCAMP2; SCAMP5; SCAPER; SCAP; SCARA3; SCARA5; SCARB1; SCARB2; SCARF2;SCCPDH; SCD5; SCD; SCFD1; SCFD2; SCG2; SCG3; SCG5; SCGB1A1; SCGB1D1;SCGB1D2; SCGB2A1; SCGB2A2; SCGB2B2; SCGB3A1; SCGB3A2; SCGN; SCHIP1;SCIN; SCLT1; SCLY; SCML2; SCML4; SCN10A; SCN11A; SCN1A; SCN1B; SCN2A;SCN2B; SCN3A; SCN3B; SCN4A; SCN4B; SCN5A; SCN7A; SCN8A; SCN9A; SCNM1;SCNN1A; SCNN1B; SCNN1D; SCNN1G; SCO1; SCO2; SCP2D1; SCPEP1; SCRIB;SCRN1; SCT; SCTR; SCUBE1; SCUBE2; SCUBE3; SCYL1; SCYL3; SDC1; SDC2;SDC3; SDC4; SDCBP2; SDCBP; SDCCAG3; SDCCAG8; SDF2; SDF2L1; SDF4; SDHAF1;SDHAF2; SDHAF4; SDHA; SDHC; SDHD; SDK1; SDK2; SDPR; SDR42E1; SDR9C7;SDS; SEC11A; SEC11C; SEC13; SEC14L1; SEC14L2; SEC14L3; SEC16B; SEC23A;SEC23B; SEC23IP; SEC24A; SEC24B; SEC24C; SEC31A; SEC61A1; SEC61G; SEC62;SEC63; SECISBP2; SECISBP2L; SECTM1; SEL1L; SELE; SELENBP1; SELL; SELP;SELPLG; SEMA3A; SEMA3B; SEMA3C; SEMA3D; SEMA3E; SEMA3F; SEMA3G; SEMA4A;SEMA4B; SEMA4D; SEMA4F; SEMA4G; SEMA5A; SEMA5B; SEMA6A; SEMA6B; SEMA6D;SEMA7A; SEMG1; SEMG2; SENP1; SENP2; SENP3; SENP5; SENP6; SENP8; SEPHS1;SEPSECS; SERAC1; SERF1A; SERGEF; SERINC1; SERINC3; SERINC5; SERP1;SERP2; SERPINA10; SERPINA11; SERPINA12; SERPINA1; SERPINA3; SERPINA4;SERPINA5; SERPINA6; SERPINA7; SERPINA9; SERPINB10; SERPINB13; SERPINB1;SERPINB2; SERPINB3; SERPINB4; SERPINB5; SERPINB6; SERPINB7; SERPINB8;SERPINB9; SERPINC1; SERPIND1; SERPINE1; SERPINE2; SERPINE3; SERPINF1;SERPINF2; SERPING1; SERPINH1; SERPINI1; SERPINI2; SERTAD1; SERTAD2;SESN1; SESN3; SETBP1; SETD1A; SETD1B; SETD2; SETD3; SETD5; SETD7; SETD8;SETDB2; SET; SETMAR; SETX; SEZ6; SEZ6L2; SEZ6L; SF1; SF3A1; SF3B1;SF3B2; SF3B6; SFI1; SFMBT1; SFMBT2; SFR1; SFRP1; SFRP2; SFRP4; SFRP5;SFSWAP; SFT2D2; SFT2D3; SFTA2; SFTA3; SFTPA1; SFTPA2; SFTPB; SFTPC;SFTPD; SFXN1; SFXN2; SFXN4; SGCA; SGCB; SGCD; SGCE; SGCG; SGCZ; SGIP1;SGK1; SGK223; SGK2; SGK3; SGMS1; SGMS2; SGOL1; SGPL1; SGPP1; SGPP2;SGSH; SGSM2; SGSM3; SGTA; SH2B1; SH2B2; SH2B3; SH2D1A; SH2D2A; SH2D3A;SH2D3C; SH2D4A; SH2D4B; SH3BGR; SH3BGRL2; SH3BGRL; SH3BP1; SH3BP2;SH3BP4; SH3BP5; SH3D19; SH3GL1; SH3GL2; SH3GL3; SH3KBP1; SH3PXD2A;SH3PXD2B; SH3RF1; SH3RF3; SH3TC2; SH3YL1; SHANK1; SHANK2; SHANK3;SHARPIN; SHBG; SHB; SHC1; SHC2; SHC3; SHC4; SHCBP1; SHF; SHFM1; SHH;SHISA2; SHISA3; SHISA6; SHISA9; SHMT1; SHMT2; SHOC2; SHOX2; SHOX; SHPK;SHPRH; SHQ1; SHROOM2; SHROOM3; SHROOM4; SIAE; SIAH1; SIAH2; SIDT1;SIGIRR; SIGLEC11; SIGLEC14; SIGLEC1; SIGLEC5; SIGLEC7; SIGLEC8; SIGLEC9;SIGMAR1; SI; SIK1; SIK2; SIK3; SIL1; SIM1; SIM2; SIN3A; SIN3B; SIPA1;SIPA1L2; SIPA1L3; SIRPA; SIRPB1; SIRPG; SIRT1; SIRT2; SIRT3; SIRT4;SIRT5; SIRT6; SIRT7; SIT1; SIVA1; SIX1; SIX2; SIX3; SIX4; SIX5; SIX6;SKA1; SKA2; SKAP1; SKAP2; SKIL; SKIV2L2; SKIV2L; SKOR1; SKOR2; SKP1;SKP2; SLA2; SLA; SLAIN2; SLAMF1; SLAMF6; SLAMF7; SLAMF8; SLBP; SLC10A1;SLC10A2; SLC10A6; SLC10A7; SLC11A1; SLC11A2; SLC12A1; SLC12A2; SLC12A3;SLC12A4; SLC12A5; SLC12A6; SLC12A7; SLC12A8; SLC12A9; SLC13A1; SLC13A2;SLC13A3; SLC13A5; SLC14A1; SLC14A2; SLC15A1; SLC15A2; SLC15A4; SLC16A10;SLC16A11; SLC16A12; SLC16A13; SLC16A1; SLC16A2; SLC16A3; SLC16A6;SLC16A7; SLC16A8; SLC16A9; SLC17A1; SLC17A2; SLC17A3; SLC17A4; SLC17A5;SLC17A6; SLC17A7; SLC17A8; SLC18A1; SLC18A2; SLC18A3; SLC19A1; SLC19A2;SLC19A3; SLC1A1; SLC1A2; SLC1A3; SLC1A4; SLC1A5; SLC1A6; SLC20A1;SLC20A2; SLC22A11; SLC22A12; SLC22A13; SLC22A14; SLC22A16; SLC22A17;SLC22A18AS; SLC22A18; SLC22A1; SLC22A23; SLC22A24; SLC22A2; SLC22A3;SLC22A4; SLC22A5; SLC22A6; SLC22A7; SLC22A8; SLC23A1; SLC23A2; SLC24A1;SLC24A2; SLC24A3; SLC24A4; SLC24A5; SLC25A10; SLC25A12; SLC25A13;SLC25A14; SLC25A15; SLC25A16; SLC25A18; SLC25A19; SLC25A1; SLC25A20;SLC25A21; SLC25A22; SLC25A23; SLC25A25; SLC25A27; SLC25A2; SLC25A36;SLC25A37; SLC25A38; SLC25A3; SLC25A40; SLC25A41; SLC25A42; SLC25A43;SLC25A45; SLC25A46; SLC25A47; SLC25A4; SLC25A52; SLC25A5; SLC25A6;SLC26A1; SLC26A2; SLC26A3; SLC26A4; SLC26A5; SLC26A6; SLC26A7; SLC26A8;SLC26A9; SLC27A1; SLC27A2; SLC27A3; SLC27A4; SLC27A5; SLC28A1; SLC28A2;SLC28A3; SLC29A1; SLC29A2; SLC29A3; SLC29A4; SLC2A10; SLC2A11; SLC2A12;SLC2A13; SLC2A14; SLC2A2; SLC2A3; SLC2A4RG; SLC2A5; SLC2A6; SLC2A8;SLC2A9; SLC30A10; SLC30A1; SLC30A3; SLC30A4; SLC30A5; SLC30A6; SLC30A7;SLC30A8; SLC30A9; SLC31A1; SLC31A2; SLC32A1; SLC33A1; SLC34A1; SLC34A2;SLC34A3; SLC35A1; SLC35A2; SLC35A3; SLC35A4; SLC35B2; SLC35B4; SLC35C1;SLC35D3; SLC35F1; SLC35F2; SLC35F3; SLC35F4; SLC35F6; SLC35G1; SLC35G2;SLC35G5; SLC35G6; SLC36A1; SLC36A2; SLC37A1; SLC37A2; SLC37A4; SLC38A1;SLC38A2; SLC38A4; SLC38A5; SLC38A6; SLC38A7; SLC38A8; SLC38A9; SLC39A10;SLC39A11; SLC39A12; SLC39A13; SLC39A14; SLC39A1; SLC39A2; SLC39A3;SLC39A4; SLC39A6; SLC39A7; SLC39A8; SLC39A9; SLC3A1; SLC3A2; SLC40A1;SLC41A1; SLC43A1; SLC43A2; SLC43A3; SLC44A1; SLC44A2; SLC44A4; SLC44A5;SLC45A2; SLC45A3; SLC45A4; SLC46A1; SLC46A2; SLC47A1; SLC48A1; SLC4A10;SLC4A11; SLC4A1AP; SLC4A1; SLC4A2; SLC4A3; SLC4A4; SLC4A5; SLC4A7;SLC4A9; SLC50A1; SLC51A; SLC51B; SLC52A1; SLC52A2; SLC52A3; SLC5A11;SLC5A12; SLC5A1; SLC5A2; SLC5A3; SLC5A4; SLC5A5; SLC5A6; SLC5A7; SLC5A8;SLC6A11; SLC6A12; SLC6A13; SLC6A14; SLC6A15; SLC6A18; SLC6A19; SLC6A1;SLC6A20; SLC6A2; SLC6A4; SLC6A5; SLC6A6; SLC6A7; SLC6A8; SLC6A9;SLC7A10; SLC7A11; SLC7A13; SLC7A14; SLC7A1; SLC7A2; SLC7A3; SLC7A4;SLC7A5; SLC7A6; SLC7A7; SLC7A8; SLC7A9; SLC8A1; SLC8A2; SLC8A3; SLC9A1;SLC9A2; SLC9A3; SLC9A3R1; SLC9A3R2; SLC9A4; SLC9A5; SLC9A6; SLC9A7;SLC9A8; SLC9A9; SLC9B1; SLC9B2; SLC9C1; SLC9C2; SLCO1A2; SLCO1B1;SLCO1B3; SLCO1B7; SLCO1C1; SLCO2A1; SLCO2B1; SLCO3A1; SLCO4A1; SLCO4C1;SLCO5A1; SLCO6A1; SLFN12; SLFN12L; SLFN14; SLFN5; SLIT1; SLIT2; SLIT3;SLITRK1; SLITRK2; SLITRK3; SLITRK5; SLITRK6; SLK; SLMAP; SLMO2; SLN;SLPI; SLTM; SLU7; SLURP1; SLX4; SLX4IP; SMAD1; SMAD2; SMAD3; SMAD4;SMAD5; SMAD6; SMAD7; SMAD9; SMAGP; SMAP1; SMARCA1; SMARCA2; SMARCA4;SMARCA5; SMARCAD1; SMARCAL1; SMARCB1; SMARCC1; SMARCC2; SMARCD1;SMARCD3; SMARCE1; SMC1A; SMC1B; SMC2; SMC3; SMC4; SMC5; SMC6; SMCHD1;SMCO4; SMCP; SMEK1; SMEK2; SMG1; SMG6; SMG8; SMIM15; SMIM19; SMIM20;SMIM21; SMIM23; SMIM5; SMN2; SMOC1; SMOC2; SMO; SMOX; SMPD1; SMPD2;SMPD3; SMPDL3A; SMPDL3B; SMPX; SMR3B; SMS; SMTN; SMTNL1; SMU1; SMUG1;SMURF1; SMURF2; SMYD1; SMYD2; SMYD3; SMYD4; SMYD5; SNAI1; SNAI2; SNAI3;SNAP23; SNAP25; SNAP29; SNAP47; SNAP91; SNAPC1; SNAPC4; SNAPC5; SNCA;SNCAIP; SNCB; SNCG; SND1; SNED1; SNF8; SNIP1; SNRK; SNRNP200; SNRNP27;SNRNP70; SNRPA; SNRPB; SNRPC; SNRPD1; SNRPD3; SNRPE; SNRPF; SNRPN;SNTA1; S NTB 1; SNTG1; SNTG2; SNUPN; SNURF; SNW1; SNX10; SNX12; SNX14;SNX16; SNX18; SNX19; SNX1; SNX20; SNX24; SNX25; SNX29; SNX2; SNX30;SNX3; SNX5; SNX9; SOAT1; SOAT2; SOBP; SOCS1; SOCS2; SOCS3; SOCS4; SOCS5;SOCS6; SOCS7; SOD1; SOD2; SOD3; SOHLH1; SOHLH2; SON; SORBS1; SORBS2;SORBS3; SORCS1; SORCS2; SORCS3; SORD; SORL1; SOS1; SOS2; SOSTDC1; SOST;SOX10; SOX11; SOX12; SOX13; SOX14; SOX15; SOX17; SOX18; SOX1; SOX21;SOX2; SOX3; SOX4; SOX5; SOX6; SOX7; SOX8; SOX9; SP100; SP110; SP140;SP1; SP2; SP3; SP4; SP5; SP6; SP7; SP8; SPA17; SPACA1; SPACA3; SPAG11A;SPAG11B; SPAG16; SPAG1; SPAG4; SPAG5; SPAG6; SPAG7; SPAG8; SPAG9; SPAM1;SPANXA2; SPANXB1; SPANXD; SPANXN4; SPARC; SPARCL1; SPAST; SPATA13;SPATA16; SPATA17; SPATA18; SPATA19; SPATA20; SPATA21; SPATA22; SPATA25;SPATA2; SPATA5; SPATA7; SPATA8; SPATA9; SPATC1; SPC24; SPC25; SPCS3;SPDEF; SPDL1; SPDYA; SPECC1; SPECC1L; SPEF2; SPEG; SPESP1; SPG11; SPG20;SPG21; SPG7; SPHK1; SPHK2; SPHKAP; SPI1; SPIB; SPIC; SPIDR; SPIN1;SPIN2A; SPINK1; SPINK2; SPINK4; SPINK5; SPINK6; SPINK7; SPINT1; SPINT2;SPNS1; SPNS2; SPO11; SPOCK1; SPOCK2; SPOCK3; SPON1; SPON2; SPOP; SPP1;SPP2; SPPL2A; SPPL2B; SPPL2C; SPPL3; SPRED1; SPRED2; SPRED3; SPR; SPRN;SPRR1A; SPRR1B; SPRR2A; SPRR2B; SPRR3; SPRTN; SPRY1; SPRY2; SPRY3;SPRY4; SPRYD7; SPSB3; SPSB4; SPTA1; SPTAN1; SPTB; SPTBN1; SPTBN2;SPTBN4; SPTBN5; SPTLC1; SPTLC2; SPTLC3; SPTSSB; SPTY2D1; SPZ1; SQLE;SQRDL; SQSTM1; SRA1; SRBD1; SRCAP; SRC; SRCIN1; SRD5A1; SRD5A2; SRD5A3;SREBF1; SREBF2; SREK1; SREK1IP1; SRFBP1; SRF; SRGAP1; SRGAP2; SRGAP3;SRGN; SRI; SRL; SRMS; SRP14; SRP19; SRP68; SRP72; SRP9; SRPK1; SRPK2;SRPRB; SRPR; SRPX2; SRPX; SRR; SRRM1; SRRM2; SRRM4; SRRT; SRSF10;SRSF11; SRSF12; SRSF1; SRSF2; SRSF3; SRSF4; SRSF5; SRSF6; SRSF7; SRSF9;SRXN1; SRY; SS18; SS18L1; SSB; SSBP1; SSBP2; SSFA2; SSH1; SSH2; SSMEM1;SSNA1; SSPN; SSPO; SSR1; SSR2; SSRP1; SSSCA1; SST; SSTR1; SSTR2; SSTR3;SSTR4; SSTR5; SSUH2; SSX1; SSX2B; SSX2IP; SSX4B; SSX5; ST13; ST14; ST18;ST20; ST3GAL1; ST3GAL2; ST3GAL4; ST3GAL5; ST3GAL6; ST5; ST6GAL1;ST6GAL2; ST6GALNAC1; ST6GALNAC2; ST6GALNAC4; ST6GALNAC6; ST7; ST7L;ST8SIA1; ST8SIA2; ST8SIA3; ST8SIA4; ST8SIA6; STAB 1; STAB2; STAC3; STAC;STAG1; STAG2; STAG3; STAM2; STAMBP; STAMBPL1; STAM; STAP1; STAP2;STARD10; STARD13; STARD3; STARD3NL; STARD5; STARD7; STARD8; STARD9;STAR; STAT1; STAT2; STAT3; STAT4; STAT5A; STAT5B; STAT6; STATH; STAU2;STBD1; STC1; STC2; STEAP1; STEAP2; STEAP3; STEAP4; STH; STIL; STIM1;STIM2; STIP1; STK10; STK11; STK11IP; STK17A; STK17B; STK19; STK24;STK25; STK26; STK31; STK32A; STK32B; STK32C; STK33; STK35; STK38L;STK39; STK3; STK4; STMN2; STMN3; STMN4; STOM; STOML1; STOML2; STOML3;STON1-GTF2A1L; STON1; STOX1; STRA13; STRA6; STRA8; STRADA; STRADB;STRAP; STRC; STRN3; STRN4; STRN; STS; STT3A; STT3B; STUB1; STX11; STX16;STX17; STX18; STX1A; STX1B; STX2; STX3; STX4; STX5; STX6; STX8; STXBP1;STXBP2; STXBP4; STXBP5; STXBP5L; STXBP6; STYK1; STYX; SUB1; SUCLA2;SUCLG1; SUCLG2; SUCNR1; SUCO; SUDS3; SUFU; SUGCT; SUGP1; SUGT1; SULF1;SULF2; SULT1A1; SULT1A2; SULT1A4; SULT1B1; SULT1C2; SULT1E1; SULT2A1;SULT2B1; SULT4A1; SUMF1; SUMF2; SUMO1; SUMO2; SUMO3; SUMO4; SUN1; SUN2;SUN3; SUOX; SUPT20H; SUPT3H; SUPT4H1; SUPT7L; SUPV3L1; SURF1; SURF4;SUSD1; SUSD2; SUSD4; SUSD6; SUV39H1; SUV39H2; SUV420H2; SUZ12; SV2B;SV2C; SVEP1; SVIL; SVIP; SVOP; SWAP70; SWT1; SYBU; SYCE1; SYCE1L; SYCP2;SYCP2L; SYCP3; SYK; SYMPK; SYN1; SYN2; SYN3; SYNCRIP; SYNDIG1; SYNE1;SYNE2; SYNE4; SYNGAP1; SYNGR1; SYNGR2; SYNJ1; SYNJ2BP; SYNJ2; SYNM;SYNPO2; SYNPO; SYNPR; SYP; SYPL1; SYPL2; SYT11; SYT12; SYT13; SYT14;SYT1; SYT4; SYT6; SYT9; SYTL1; SYTL2; SYTL5; SYVN1; TAAR1; TAAR2; TAAR5;TAAR6; TAB 1; TAB2; TAB 3; TAC1; TAC3; TAC4; TACC1; TACC2; TACC3; TACO1;TACR1; TACR2; TACR3; TADA1; TADA2A; TADA3; TAF15; TAF1B; TAF1C; TAF1D;TAF1; TAF2; TAF3; TAF4B; TAF4; TAF5L; TAF6; TAF7; TAF7L; TAF8; TAF9;TAGAP; TAGLN2; TAGLN; TALI; TAL2; TALDO1; TAMM41; TANC1; TANC2; TANGO2;TANK; TAOK1; TAOK2; TAOK3; TAP1; TAP2; TAPBP; TAPBPL; TARBP1; TARBP2;TARP; TARS; TARSL2; TAS2R10; TAS2R13; TAS2R14; TAS2R16; TAS2R1; TAS2R38;TAS2R50; TAS2R60; TAS2R9; TASP1; TATDN1; TAT; TAX1BP1; TAX1BP3; TAZ;TBATA; TBC1D15; TBC1D16; TBC1D1; TBC1D20; TBC1D22A; TBC1D22B; TBC1D24;TBC1D25; TBC1D2; TBC1D32; TBC1D3C; TBC1D3F; TBC1D4; TBC1D5; TBC1D7;TBC1D8; TBC1D9; TBCA; TBCC; TBCD; TBCE; TBCEL; TBK1; TBKBP1; TBL1X;TBL1XR1; TBL1Y; TBL2; TBL3; TBP; TBPL1; TBPL2; TBR1; TBRG1; TBX10;TBX18; TBX19; TBX1; TBX20; TBX21; TBX22; TBX2; TBX3; TBX4; TBX5; TBX6;TBXA2R; TBXAS1; TCAIM; TCAP; TCEA1; TCEA2; TCEA3; TCEAL1; TCEAL2;TCEAL4; TCEAL7; TCEB1; TCEB2; TCEB3C; TCERG1; TCERG1L; TCF12; TCF15;TCF19; TCF20; TCF21; TCF25; TCF3; TCF4; TCF7; TCF7L1; TCF7L2; TCFL5;TCHH; TCHP; TCIRG1; TCL1A; TCL1B; TCN1; TCN2; TCOF1; TCP10; TCP10L2;TCP11L1; TCP1; TCTA; TCTE1; TCTN1; TCTN2; TCTN3; TDGF1; TDG; TDO2; TOP1;TOP2; TDRD1; TDRD3; TDRD5; TDRD6; TDRD7; TDRD9; TDRKH; TDRP; TEAD1;TEAD2; TEAD3; TEAD4; TEC; TECPR2; TECR; TECRL; TECTA; TEF; TEFM; TEK;TEKT1; TEKT5; TELO2; TENM1; TENM2; TENM3; TENM4; TEP1; TEPP; TERF1;TERF2; TERF2IP; TERT; TESC; TES; TESPA1; TET1; TET2; TET3; TEX101;TEX11; TEX14; TEX15; TEX264; TEX29; TEX30; TEX35; TEX40; TFAM; TFAP2A;TFAP2B; TFAP2C; TFAP4; TFB1M; TFB2M; TFCP2; TFDP1; TFDP2; TFDP3; TFE3;TFEB; TFEC; TFF1; TFF2; TFF3; TFG; TF; TFIP11; TFPI2; TFPI; TFPT; TFR2;TFRC; TGFA; TGFB1; TGFB1I1; TGFB2; TGFB3; TGFBI; TGFBR1; TGFBR2;TGFBRAP1; TG; TGIF1; TGIF2-C20orf24; TGIF2; TGIF2LX; TGM1; TGM2; TGM3;TGM4; TGM5; TGM6; TGM7; TGOLN2; TGS1; THADA; THAP10; THAP11; THAP1;THAP2; THAP6; THBD; THBS1; THBS2; THBS3; THBS4; THEG; THEM4; THEM5;THEM6; THEMIS2; THEMIS; THG1L; TH; THNSL1; THNSL2; THOC1; THOC2; THOC5;THOC6; T; THOP1; THPO; THRA; THRB; THRSP; THSD1; THSD4; THSD7A; THYN1;TIA1; TIAF1; TIAL1; TIAM1; TIAM2; TICAM1; TICAM2; TICRR; TIFA; TIGD2;TIGIT; TIMD4; TIMELESS; TIMM10; TIMM17A; TIMM21; TIMM22; TIMM23; TIMM44;TIMM50; TIMM8A; TIMM8B; TIMMDC1; TIMP1; TIMP2; TIMP3; TIMP4; TINAG;TINF2; TIPARP; TIPIN; TIPRL; TIRAP; TJP1; TJP2; TJP3; TK1; TK2; TKT;TKTL1; TKTL2; TLDC1; TLE1; TLE2; TLE3; TLE4; TLE6; TLK1; TLK2; TLL1;TLL2; TLN1; TLN2; TLR10; TLR1; TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8;TLR9; TLX1; TLX2; TLX3; TM4SF1; TM4SF20; TM4SF4; TM4SF5; TM6SF2; TM7SF2;TM9SF2; TM9SF4; TMBIM4; TMBIM6; TMC1; TMC2; TMC3; TMC5; TMC6; TMC8;TMCC1; TMCC2; TMCC3; TMCO1; TMCO4; TMCO5A; TMED10; TMED1; TMED2; TMED3;TMED4; TMED7; TMED7-TICAM2; TMED9; TMEFF1; TMEFF2; TMEM100; TMEM101;TMEM105; TMEM106B; TMEM108; TMEM114; TMEM115; TMEM117; TMEM11; TMEM126A;TMEM127; TMEM128; TMEM132A; TMEM132B; TMEM132C; TMEM132D; TMEM132E;TMEM134; TMEM135; TMEM138; TMEM150B; TMEM151A; TMEM151B; TMEM154;TMEM158; TMEM160; TMEM161B; TMEM163; TMEM165; TMEM169; TMEM170A;TMEM171; TMEM173; TMEM175; TMEM176B; TMEM178A; TMEM182; TMEM183A;TMEM184C; TMEM185A; TMEM187; TMEM189; TMEM189-UBE2V1; TMEM18; TMEM199;TMEM200A; TMEM205; TMEM207; TMEM209; TMEM213; TMEM215; TMEM216; TMEM217;TMEM219; TMEM220; TMEM229A; TMEM231; TMEM233; TMEM237; TMEM241; TMEM244;TMEM245; TMEM259; TMEM25; TMEM261; TMEM27; TMEM2; TMEM30A; TMEM30B;TMEM37; TMEM38A; TMEM38B; TMEM39A; TMEM40; TMEM43; TMEM45A; TMEM47;TMEM50B; TMEM55A; TMEM57; TMEM5; TMEM60; TMEM62; TMEM63A; TMEM67;TMEM70; TMEM74B; TMEM79; TMEM87A; TMEM88; TMEM89; TMEM8B; TMEM95;TMEM97; TMEM98; TMF1; TMIE; TMIGD2; TMIGD3; TMLHE; TMOD1; TMOD2; TMOD3;TMOD4; TMPO; TMPRSS11A; TMPRSS11B; TMPRSS11D; TMPRSS11E; TMPRSS13;TMPRSS15; TMPRSS2; TMPRSS3; TMPRSS4; TMPRSS6; TMPRSS7; TMPRSS9; TMSB10;TMSB15B; TMSB4X; TMTC1; TMTC2; TMTC3; TMX1; TMX2; TMX3; TNC; TNFAIP1;TNFAIP2; TNFAIP3; TNFAIP6; TNFAIP8; TNFAIP8L2; TNFAIP8L3; TNF;TNFRSF10A; TNFRSF10B; TNFRSF10C; TNFRSF10D; TNFRSF11A; TNFRSF11B;TNFRSF12A; TNFRSF13B; TNFRSF13C; TNFRSF14; TNFRSF19; TNFRSF1A; TNFRSF1B;TNFRSF21; TNFRSF6B; TNFRSF8; TNFSF10; TNFSF11; TNFSF12; TNFSF12-TNFSF13;TNFSF13B; TNFSF13; TNFSF14; TNFSF15; TNFSF18; TNFSF4; TNFSF8; TNFSF9;TNIK; TNIP1; TNIP2; TNIP3; TNK1; TNK2; TNKS2; TNKS; TNMD; TNNC1; TNN;TNNI1; TNNI2; TNNI3; TNNT1; TNNT2; TNNT3; TNP1; TNP2; TNPO1; TNPO2;TNPO3; TNRC18; TNRC6A; TNRC6B; TNR; TNS1; TNS2; TNS3; TNS4; TNXB; TOB1;TOB2; TOLLIP; TOM1; TOM1L1; TOMM20; TOMM34; TOMM40; TOMM70A; TONSL;TOP1; TOP2A; TOP2B; TOP3A; TOP3B; TOPBP1; TOPORS; TOR1A; TOR1AIP1;TOR1AIP2; TOR1B; TOR2A; TOX2; TOX3; TOX4; TOX; TP53AIP1; TP53BP1;TP53BP2; TP53; TP53I11; TP53I13; TP53I3; TP53INP1; TP53INP2; TP53RK;TP53TG3C; TP63; TP73; TPBG; TPCN1; TPCN2; TPD52; TPD52L1; TPD52L2;TPGS2; TPH1; TPH2; TPI1; TPK1; TPM1; TPM2; TPM3; TPM4; TPMT; TPO; TPP1;TPP2; TPPP2; TPPP3; TPPP; TPRG1; TPR; TPRN; TPSAB1; TPSB2; TPSD1; TPSG1;TPT1; TPTE2; TPTE; TPX2; TRA2A; TRA2B; TRABD2A; TRABD; TRADD; TRAF1;TRAF2; TRAF3; TRAF3IP1; TRAF3IP2; TRAF4; TRAF5; TRAF6; TRAF7; TRAFD1;TRAK1; TRAK2; TRAM1; TRAM1L1; TRAM2; TRAP1; TRAPPC10; TRAPPC11; TRAPPC1;TRAPPC2; TRAPPC4; TRAPPC9; TRAT1; TRDMT1; TRDN; TREH; TREM1; TREM2;TREML1; TREML2; TRERF1; TREX1; TREX2; TRHDE; TRH; TRHR; TRIAP1; TRIB1;TRIB2; TRIB3; TRIM10; TRIM11; TRIM13; TRIM15; TRIM16; TRIM17; TRIM21;TRIM22; TRIM23; TRIM24; TRIM25; TRIM26; TRIM27; TRIM28; TRIM29; TRIM2;TRIM31; TRIM32; TRIM34; TRIM35; TRIM36; TRIM37; TRIM38; TRIM39; TRIM3;TRIM40; TRIM42; TRIM44; TRIM50; TRIM56; TRIM58; TRIM59; TRIM5; TRIM62;TRIM66; TRIM68; TRIM69; TRIM6-TRIM34; TRIM71; TRIM72; TRIM73; TRIM74;TRIM8; TRIM9; TRIOBP; TRIO; TRIP10; TRIP11; TRIP13; TRIP4; TRIP6; TRIQK;TRMT10A; TRMT12; TRMT1; TRMT44; TRMT5; TRMU; TRO; TROVE2; TRPA1; TRPC1;TRPC3; TRPC4AP; TRPC4; TRPC5; TRPC6; TRPC7; TRPM1; TRPM2; TRPM3; TRPM4;TRPM5; TRPM6; TRPM7; TRPM8; TRPS1; TRPV1; TRPV2; TRPV3; TRPV4; TRPV5;TRPV6; TRRAP; TSACC; TSC1; TSC22D1; TSC22D3; TSC22D4; TSC2; TSEN2;TSEN34; TSEN54; TSFM; TSG101; TSGA10; TSHR; TSHZ1; TSHZ2; TSHZ3; TSLP;TSNAX; TSN; TSPAN10; TSPAN11; TSPAN12; TSPAN13; TSPAN14; TSPAN16;TSPAN18; TSPAN31; TSPAN32; TSPAN33; TSPAN4; TSPAN6; TSPAN7; TSPAN8;TSPAN9; TSPEAR; TSPO2; TSPO; TSPY10; TSPY1; TSPY3; TSPY4; TSPYL1;TSPYL2; TSPYL4; TSPYL5; TSR1; TSSC1; TSSK1B; TSSK2; TSSK4; TSTA3; TSTD1;TST; TTBK1; TTBK2; TTC12; TTC17; TTC19; TTC1; TTC21B; TTC28; TTC29;TTC37; TTC39A; TTC39B; TTC3; TTC5; TTC6; TTC7A; TTC7B; TTC8; TTC9B;TTC9C; TTC9; TTF1; TTF2; TTI1; TTI2; TTK; TTL; TTLL10; TTLL11; TTLL12;TTLL1; TTLL3; TTLL4; TTLL5; TTLL6; TTLL7; TTLL8; TTLL9; TTPA; TTR;TTYH1; TTYH2; TUBA1A; TUBA1B; TUBA1C; TUBA3D; TUBA4A; TUBAE; TUBB1;TUBB2A; TUBB2B; TUBB3; TUBB4A; TUBB4B; TUBB6; TUBB; TUBD1; TUBE1; TUBG1;TUBG2; TUBGCP2; TUBGCP3; TUBGCP4; TUBGCP5; TUBGCP6; TUB; TUFM; TUFT1;TULP1; TULP2; TULP3; TULP4; TUSC1; TUSC2; TUSC3; TUSC5; TUT1; TVP23B;TWF1; TWIST1; TWIST2; TWSG1; TXK; TXLNG; TXN2; TXNDC15; TXNDC16;TXNDC17; TXNDC5; TXN; TXNL1; TXNRD2; TXNRD3NB; TYK2; TYMP; TYMS; TYR;TYRO3; TYROBP; TYRP1; TYSND1; TYW1B; U2AF1; U2AF2; UACA; UAP1; UBA1;UBA2; UBA3; UBA7; UBAC1; UBAC2; UBAP1; UBAP2; UBASH3A; UBASH3B; UBB;UBC; UBD; UBE2A; UBE2B; UBE2C; UBE2D1; UBE2D2; UBE2D3; UBE2E1; UBE2E2;UBE2E3; UBE2G1; UBE2G2; UBE2H; UBE2I; UBE2J1; UBE2K; UBE2L3; UBE2L6;UBE2M; UBE2N; UBE2Q2; UBE2QL1; UBE2R2; UBE2S; UBE2T; UBE2U; UBE2V1;UBE2V2; UBE2Z; UBE3A; UBE3B; UBE3C; UBE4A; UBE4B; UBIAD1; UBL3; UBL4A;UBL5; UBL7; UBLCP1; UBN1; UBOX5; UBP1; UBQLN1; UBQLN2; UBQLNL; UBR1;UBR3; UBR4; UBR5; UBR7; UBTD2; UBTF; UBXN1; UBXN2A; UBXN2B; UBXN4;UCHL1; UCHL3; UCHL5; UCK1; UCK2; UCKL1; UCMA; UCN2; UCN3; UCN; UCP1;UCP2; UCP3; UEVLD; UFD1L; UFL1; UFM1; UGCG; UGDH; UGGT1; UGGT2; UGP2;UGT1A10; UGT1A1; UGT1A3; UGT1A4; UGT1A5; UGT1A6; UGT1A7; UGT1A8; UGT1A9;UGT2A1; UGT2A2; UGT2A3; UGT2B10; UGT2B 11; UGT2B15; UGT2B28; UGT2B4;UGT2B7; UGT3A2; UGT8; UHMK1; UHRF1BP1; UHRF1; UHRF2; UIMC1; ULBP1;ULBP2; ULBP3; ULK1; ULK2; ULK3; ULK4; UMOD; UMODL1; UMPS; UNC119;UNC13A; UNC13B; UNC13C; UNC13D; UNC45A; UNC45B; UNC5A; UNC5B; UNC5C;UNC5D; UNC79; UNC93A; UNC93B1; UNG; UPB1; UPF1; UPF2; UPF3A; UPF3B;UPK1A; UPK1B; UPK2; UPK3A; UPP1; UPP2; UPRT; UQCC1; UQCC2; UQCRB;UQCRC1; UQCRC2; UQCRFS1; UQCRQ; URB2; URGCP; URI1; URM1; UROC1; UROD;UROS; USB1; USE1; USF1; USF2; USH1C; USH1G; USH2A; USO1; USP10; USP11;USP12; USP13; USP14; USP15; USP17L2; USP17L30; USP18; USP20; USP22;USP25; USP26; USP28; USP2; USP32; USP33; USP36; USP37; USP3; USP40;USP42; USP43; USP44; USP46; USP48; USP49; USP4; USPS; USP6; USP6NL;USP7; USPS; USP9X; USP9Y; USPL1; UST; UTF1; UTP14A; UTP14C; UTP20; UTRN;UTS2B; UTS2; UTS2R; UTY; UVRAG; UVSSA; UXS1; UXT; VAC14; VAMP1; VAMP2;VAMP4; VAMP7; VAMP8; VANGL2; VAPA; VAPB; VARS2; VARS; VASH1; VASH2;VASP; VAT1; VAT1L; VAV1; VAV2; VAV3; VAX1; VAX2; VBP1; VCAN; VCL; VCP;VCX2; VCX3A; VCX3B; VCX; VCY; VDAC1; VDAC2; VDR; VEGFA; VEGFB; VEGFC;VENTX; VEPH1; VEZT; VGF; VGLL1; VGLL2; VGLL3; VGLL4; VHL; VHLL; VIL1;VIM; VIPAS39; VIP; VIPR1; VIPR2; VIT; VKORC1; VLDLR; VMA21; VMO1; VMP1;VN1R2; VN1R4; VNN1; VNN2; VNN3; VOPP1; VPRBP; VPREB1; VPREB3; VPS11;VPS13A; VPS13B; VPS13C; VPS26A; VPS28; VPS33A; VPS33B; VPS35; VPS36;VPS37A; VPS37B; VPS37C; VPS39; VPS41; VPS4A; VPS4B; VPS51; VPS52; VPS53;VPS54; VPS72; VPS8; VRK1; VRK2; VSIG10; VSIG1; VSIG2; VSIG4; VSNL1;VSTM1; VSX1; VSX2; VTA1; VTCN1; VTI1A; VTI1B; VTN; VWA2; VWA3A; VWA3B;VWA5A; VWA5B1; VWA7; VWA8; VWCE; VWDE; VWF; WAPAL; WARS2; WARS; WASF1;WASF3; WASH1; WAS; WASL; WBP1L; WBP2; WBSCR17; WBSCR22; WDFY2; WDFY4;WDHD1; WDPCP; WDR11; WDR12; WDR17; WDR19; WDR1; WDR20; WDR26; WDR31;WDR34; WDR35; WDR36; WDR37; WDR43; WDR45B; WDR45; WDR46; WDR48; WDR49;WDR4; WDR55; WDR5; WDR60; WDR62; WDR64; WDR66; WDR70; WDR72; WDR74;WDR76; WDR78; WDR7; WDR81; WDR83; WDR86; WDR93; WEE1; WFDC1; WFDC2;WFS1; WHSC1; WHSC1L1; WIF1; WIPF1; WIPF2; WIPF3; WIPI1; WIPI2; WISP1;WISP2; WISP3; WLS; WNK1; WNK2; WNK3; WNK4; WNT10A; WNT10B; WNT11; WNT16;WNT1; WNT2B; WNT2; WNT3A; WNT3; WNT4; WNT5A; WNT5B; WNT6; WNT7A; WNT7B;WNT8A; WNT8B; WNT9A; WNT9B; WRAP53; WRB; WRN; WRNIP1; WSB1; WSCD1;WSCD2; WT1; WTAP; WTIP; WWC1; WWC2; WWOX; WWP1; WWP2; WWTR1; XAB2; XAF1;XAGE1B; XAGE1E; XBP1; XCL1; XCL2; XCR1; XDH; XG; XIAP; XIRP1; XIRP2; XK;XKR4; XKR6; XKR9; XPA; XPC; XPNPEP1; XPNPEP2; XPNPEP3; XPO1; XPO4; XPO5;XPO6; XPO7; XPR1; XRCC1; XRCC2; XRCC3; XRCC4; XRCC5; XRCC6BP1; XRCC6;XRN1; XRN2; XRRA1; XXYLT1; XYLB; XYLT1; XYLT2; YAE1D1; YAP1; YARS2;YBX2; YBX3; YDJC; YEATS4; YES1; YIF1A; YIPF1; YIPF3; YIPF5; YKT6; YLPM1;YME1L1; YPEL1; YPEL2; YPEL3; YPEL4; YPEL5; YTHDC1; YTHDC2; YWHAB; YWHAE;YWHAG; YWHAH; YWHAQ; YWHAZ; YY1AP1; YY1; ZACN; ZAK; ZAP70; ZAR1; ZAR1L;ZASP; ZBED1; ZBED4; ZBED5; ZBP1; ZBTB10; ZBTB12; ZBTB14; ZBTB16; ZBTB17;ZBTB18; ZBTB20; ZBTB21; ZBTB22; ZBTB24; ZBTB2; ZBTB32; ZBTB33; ZBTB34;ZBTB38; ZBTB41; ZBTB46; ZBTB48; ZBTB49; ZBTB4; ZBTB5; ZBTB7C; ZBTB9;ZC2HC1B; ZC3H10; ZC3H11A; ZC3H12C; ZC3H12D; ZC3H14; ZC3H15; ZC3H3;ZC3H4; ZC3H7A; ZC3H7B; ZC3HAV1; ZC3HC1; ZC4H2; ZCCHC11; ZCCHC12;ZCCHC14; ZCCHC2; ZCCHC3; ZCCHC6; ZCCHC8; ZCRB 1; ZCWPW1; ZDB F2;ZDHHC11; ZDHHC12; ZDHHC13; ZDHHC14; ZDHHC15; ZDHHC17; ZDHHC1; ZDHHC2;ZDHHC7; ZDHHC8; ZDHHC9; ZEB1; ZEB2; ZFAND3; ZFAND5; ZFAND6; ZFAT;ZFC3H1; ZFHX2; ZFHX3; ZFHX4; ZFP1; ZFP30; ZFP36; ZFP36L1; ZFP36L2;ZFP37; ZFP42; ZFP57; ZFP64; ZFP82; ZFP91; ZFPM1; ZFPM2; ZFR2; ZFR; ZFX;ZFY; ZFYVE19; ZFYVE21; ZFYVE26; ZFYVE27; ZFYVE28; ZFYVE9; ZG16B; ZGLP1;ZGPAT; ZHX1; ZHX2; ZIC1; ZIC2; ZIC3; ZIC4; ZIC5; ZIK1; ZIM2; ZKSCAN1;ZKSCAN3; ZKSCAN7; ZMAT3; ZMAT4; ZMIZ1; ZMYM2; ZMYM3; ZMYM4; ZMYM5;ZMYND10; ZMYND11; ZMYND8; ZNF106; ZNF107; ZNF10; ZNF112; ZNF121; ZNF131;ZNF132; ZNF133; ZNF141; ZNF143; ZNF146; ZNF148; ZNF154; ZNF160; ZNF169;ZNF175; ZNF177; ZNF182; ZNF184; ZNF185; ZNF189; ZNF197; ZNF202; ZNF205;ZNF20; ZNF212; ZNF214; ZNF215; ZNF217; ZNF224; ZNF22; ZNF230; ZNF236;ZNF239; ZNF23; ZNF248; ZNF24; ZNF253; ZNF260; ZNF263; ZNF264; ZNF266;ZNF267; ZNF268; ZNF273; ZNF274; ZNF276; ZNF277; ZNF280B; ZNF280D;ZNF281; ZNF282; ZNF286B; ZNF296; ZNF2; ZNF300; ZNF311; ZNF318; ZNF320;ZNF322; ZNF32; ZNF330; ZNF331; ZNF334; ZNF335; ZNF343; ZNF350; ZNF354A;ZNF35; ZNF365; ZNF366; ZNF367; ZNF382; ZNF383; ZNF384; ZNF385A; ZNF385B;ZNF385D; ZNF391; ZNF395; ZNF398; ZNF407; ZNF410; ZNF415; ZNF419; ZNF41;ZNF423; ZNF430; ZNF432; ZNF433; ZNF438; ZNF443; ZNF444; ZNF44; ZNF451;ZNF45; ZNF462; ZNF469; ZNF483; ZNF490; ZNF492; ZNF496; ZNF501; ZNF507;ZNF512B; ZNF512; ZNF513; ZNF516; ZNF519; ZNF521; ZNF536; ZNF555; ZNF559;ZNF568; ZNF569; ZNF577; ZNF580; ZNF581; ZNF582; ZNF583; ZNF585B; ZNF592;ZNF596; ZNF606; ZNF607; ZNF608; ZNF615; ZNF618; ZNF627; ZNF629; ZNF639;ZNF644; ZNF645; ZNF646; ZNF652; ZNF654; ZNF664; ZNF667; ZNF668; ZNF674;ZNF676; ZNF678; ZNF683; ZNF687; ZNF689; ZNF703; ZNF704; ZNF706; ZNF711;ZNF716; ZNF717; ZNF746; ZNF74; ZNF750; ZNF763; ZNF764; ZNF765; ZNF76;ZNF774; ZNF776; ZNF778; ZNF784; ZNF79; ZNF7; ZNF800; ZNF804A; ZNF804B;ZNF80; ZNF812; ZNF813; ZNF816; ZNF81; ZNF823; ZNF827; ZNF829; ZNF831;ZNF91; ZNF92; ZNF93; ZNF98; ZNFX1; ZNHIT2; ZNHIT3; ZNRD1; ZNRF3; ZP1;ZP4; ZPB P2; ZPLD1; ZPR1; ZRANB3; ZRS R2; ZSCAN18; ZSCAN22; ZSCAN26;ZSCAN31; ZSCAN32; ZSCAN9; ZSWIM2; ZSWIM6; ZW10; ZWILCH; ZWINT; ZYX;ZZEF1; and ZZZ3.
 4. The RNA according to claim 1, wherein thetherapeutic protein comprises an amino acid sequence selected from thegroup consisting amino acid sequences according to any one of SEQ ID NO:1 to
 13057. 5. (canceled)
 6. The RNA according to claim 1, wherein theRNA is an mRNA, a viral RNA or a replicon RNA.
 7. The RNA according toclaim 1, wherein the RNA is a modified RNA.
 8. The RNA according toclaim 7, wherein the the G/C content of the at least one coding sequenceof the RNA is increased compared to the G/C content of the correspondingcoding sequence of the corresponding wild type RNA, and/or wherein the Ccontent of the at least one coding sequence of the RNA is increasedcompared to the C content of the corresponding coding sequence of thecorresponding wild type RNA, and/or wherein the codons in the at leastone coding sequence of the RNA are adapted to human codon usage, whereinthe codon adaptation index (CAI) is preferably increased or maximised inthe at least one coding sequence of the RNA, wherein the amino acidsequence encoded by the RNA is preferably not being modified compared tothe amino acid sequence encoded by the corresponding wild type RNA.9-10. (canceled)
 11. The RNA according to claim 1, which comprises a5′-CAP structure, a 5′-untranslated region (5′-UTR), and/or at least one3′-untranslated region element (3′-UTR element).
 12. The RNA accordingto claim 1, which comprises at least one histone stem-loop. 13-14.(canceled)
 15. The RNA according to claim 12, wherein the at least onehistone stem loop comprises a nucleic acid sequence according to SEQ IDNO:
 2451. 16. The RNA according to claim 1, wherein the at least one RNAcomprises a poly(A) sequence, preferably comprising 10 to 200, 10 to100, 40 to 80 or 50 to 70 adenosine nucleotides, and/or a poly(C)sequence, preferably comprising 10 to 200, 10 to 100, 20 to 70, 20 to 60or 10 to 40 cytosine nucleotides.
 17. The RNA according to claim 1,which comprises, in 5′ to 3′ direction, the following elements: a) a5′-CAP structure, b) at least one coding sequence comprising a nucleicacid sequence selected from the group consisting of nucleic acidsequences according to any one of SEQ ID NO: 13058 to 78342 or a havingat least 80% identity to any one of SEQ ID NO: 13058 to 78342, c) apoly(A) tail, d) optionally a poly(C) tail, e) optionally a histonestem-loop.
 18. The RNA according to claim 11, which comprises a 3′-UTRelement and wherein the 3′-UTR element comprises a nucleic acid sequencederived from a 3′-UTR of a gene.
 19. The RNA according to claim 18,wherein the 3′-UTR element comprises a nucleic acid sequence derivedfrom a 3′-UTR of a gene selected from the group consisting of an albumingene, an α-globin gene, a β-globin gene, a tyrosine hydroxylase gene, alipoxygenase gene, and a collagen alpha gene, or from a homolog, afragment or a variant thereof.
 20. The RNA according to claim 18,wherein the 3′-UTR element comprises a nucleic acid sequence derivedfrom a 3′-UTR of an α-globin gene. 21-36. (canceled)
 37. A kit of parts,comprising the RNA according to claim 1 and optionally a liquid vehiclefor solubilising and optionally technical instructions with informationon the administration and dosage of the RNA or the composition. 38-47.(canceled)
 48. A method of treating or preventing a disorder, whereinthe method comprises administering to a subject in need thereof aneffective amount of the RNA according to claim
 1. 49. The methodaccording to claim 48, wherein the disorder is a disease, disorder orcondition amenable to treatment by expression of the encoded peptide orprotein.
 50. The method according to claim 48, wherein the disorder is adisease, disorder or condition indicated in Table 1.